bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–05–26
94 papers selected by
Viktor Korolchuk, Newcastle University
  1. Failure of Autophagy in Pompe Disease.
  2. The Role of Autophagy in Vascular Endothelial Cell Health and Physiology.
  3. KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
  4. Leucyl-tRNA synthetase contributes to muscle weakness through mTORC1 activation and autophagy suppression in a mouse model of Duchenne Muscular Dystrophy.
  5. Autophagy and metabolic aging: Current understanding and future applications.
  6. ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.
  7. Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.
  8. The autophagy-lysosome pathway: a potential target in the chemical and gene therapeutic strategies for Parkinson's disease.
  9. AMPK regulates phagophore-to-autophagosome maturation.
  10. Chaperone-Mediated Autophagy in Brain Injury: A Double-Edged Sword with Therapeutic Potentials.
  11. mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway.
  12. Cellular depletion of major cathepsin proteases reveals their concerted activities for lysosomal proteolysis.
  13. eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition.
  14. PKD2 regulates autophagy and forms a protein complex with BECN1 at the primary cilium of hypothalamic neuronal cells.
  15. The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux.
  16. Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.
  17. Beclin-mediated Autophagy Drives Dorsal Longitudinal Flight Muscle Histolysis in the Variable Field Cricket, Gryllus lineaticeps.
  18. Upregulation of neuronal ER-phagy improves organismal fitness and alleviates APP toxicity.
  19. A synchronized symphony: Intersecting roles of ubiquitin proteasome system and autophagy in cellular degradation.
  20. Ethanol disrupts hepatocellular lipophagy by altering Rab5-centric LD-lysosome trafficking.
  21. mTORC1 and BMP-Smad1/5 Regulation of Serum-Stimulated Myotube Hypertrophy: A Role for Autophagy.
  22. Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy.
  23. Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model.
  24. Targeting the autophagy-miRNA axis in prostate cancer: toward novel diagnostic and therapeutic strategies.
  25. Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
  26. Traumatic brain injury heterogeneity affects cell death and autophagy.
  27. VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
  28. Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases.
  29. Autophagy-associated non-coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis.
  30. PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.
  31. Propolis as an autophagy modulator in relation to its roles in redox balance and inflammation regulation.
  32. Gonococcal OMVs induce epithelial cell mitophagy in a dual PorB-dependent manner to enhance intracellular survival.
  33. Exploring lysosomal biology: current approaches and methods.
  34. Research progress on the role of autophagy in the development of varicocele.
  35. Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes.
  36. Accurate automated segmentation of autophagic bodies in yeast vacuoles using cellpose 2.0.
  37. Lysine-specific demethylase 1 (LSD1) participate in porcine early embryonic development by regulating cell autophagy and apoptosis through the mTOR signaling pathway.
  38. Autophagy-related ncRNAs: Regulatory Roles and Potential Therapeutic Effects in Digestive System Neoplasms.
  39. High salt diet induces cognitive impairment and is linked to the activation of IGF1R/mTOR/p70S6K signaling.
  40. Bunyavirus SFTSV NSs utilizes autophagy to escape the antiviral innate immune response.
  41. ER-to-lysosome-associated degradation acts as failsafe mechanism upon ERAD dysfunction.
  42. Recent insights about autophagy in pancreatitis.
  43. Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.
  44. Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?
  45. Inhibition of ERK1/2 or CRMP2 Disrupts Alcohol Memory Reconsolidation and Prevents Relapse in Rats.
  46. Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model.
  47. Sensitivity of substrate translocation in chaperone-mediated autophagy to Alzheimer's disease progression.
  48. LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome positive cancer cells.
  49. Autophagy-deficient macrophages exacerbate cisplatin-induced mitochondrial dysfunction and kidney injury via miR-195a-5p-SIRT3 axis.
  50. Tris(2-ethylhexyl) phosphate induces cytotoxicity in TM3 Leydig cells by modulating autophagy and endoplasmic reticulum stress.
  51. Lon1 Inactivation Downregulates Autophagic Flux and Brassinosteroid Biogenesis, Modulating Mitochondrial Proportion and Seed Development in Arabidopsis.
  52. Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.
  53. The Metabolic and Lipidomic Fingerprint of Torin1 Exposure in Mouse Embryonic Fibroblasts Using Untargeted Metabolomics.
  54. Chloramphenicol alleviates 5-fluorouracil-induced cellular senescence through activation of autophagy.
  55. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  56. A role of dentate gyrus mechanistic target of rapamycin activation in epileptogenesis in a mouse model of posttraumatic epilepsy.
  57. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
  58. Periodontopathogen-Related Cell Autophagy-A Double-Edged Sword.
  59. Exploring the role of autophagy in psoriasis pathogenesis: Insights into sustained inflammation and dysfunctional keratinocyte differentiation.
  60. USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D.
  61. Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.
  62. Methods for investigating STAT3 regulation of lysosomal function in mammary epithelial cells.
  63. Artificially transplanted mitochondria in endothelial cells promote mitophagy.
  64. Ca2+-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress.
  65. EV71 5'UTR interacts with 3D protein affecting replication through the AKT-mTOR pathway.
  66. p20BAP31 Induces Autophagy in Colorectal Cancer Cells by Promoting PERK-Mediated ER Stress.
  67. mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.
  68. An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.
  69. Autophagy in Osteoarthritis: A Double-Edged Sword in Cartilage Aging and Mechanical Stress Response: A Systematic Review.
  70. Biomechanical activation of keloid fibroblasts promotes lysosomal remodelling and exocytosis.
  71. Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson's disease.
  72. Structure and mechanism of lysosome transmembrane acetylation by HGSNAT.
  73. Sestrin2 remedies neuroinflammatory response by inhibiting A1 astrocyte conversion via autophagy.
  74. Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy.
  75. Urolithin A, induces apoptosis and autophagy crosstalk in Oral Squamous Cell Carcinoma via mTOR /AKT/ERK1/2 pathway.
  76. SIRT3 and RORα are two prospective targets against mitophagy during simulated ischemia/reperfusion injury in H9c2 cells.
  77. Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis.
  78. The Spermine Oxidase/Spermine Axis Coordinates ATG5-Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis.
  79. HACD3 Prevents PB1 from Autophagic Degradation to Facilitate the Replication of Influenza A Virus.
  80. Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis.
  81. Pharmaceutical therapies targeting autophagy for the treatment of age-related macular degeneration.
  82. Crizotinib enhances PARP inhibitor efficacy in ovarian cancer cells and xenograft models by inducing autophagy.
  83. MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
  84. Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.
  85. Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer.
  86. Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.
  87. Detection of ribophagy in yeast and mammals.
  88. Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.
  89. Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis.
  90. Tectorigenin improves metabolic dysfunction-associated steatohepatitis by down-regulating tRF-3040b and promoting mitophagy to inhibit pyroptosis pathway.
  91. Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice.
  92. AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.
  93. Molecular mechanisms of aging and anti-aging strategies.
  94. Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.
  1. Biomolecules. 2024 May 13. pii: 573. [Epub ahead of print]14(5):
    Failure of Autophagy in Pompe Disease.
    Hung Do, Naresh K Meena, Nina Raben.
      Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.
    Keywords:  Pompe disease; autophagy; enzyme replacement therapy; glycogen degradation; lysosome; muscle
    DOI:  https://doi.org/10.3390/biom14050573
  2. Cells. 2024 May 11. pii: 825. [Epub ahead of print]13(10):
    The Role of Autophagy in Vascular Endothelial Cell Health and Physiology.
    Meghan Hu, Joseph M Ladowski, He Xu.
      Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
    Keywords:  atherosclerosis; autophagy; endothelial cells; inflammation; mitophagy; therapeutics; vascular disease
    DOI:  https://doi.org/10.3390/cells13100825
  3. Sci Rep. 2024 05 22. 14(1): 11721
    KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
    Capucine de Talhouët, Noemi Esteras, Marc P M Soutar, Benjamin O'Callaghan, Helene Plun-Favreau.
      It has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson's Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.
    Keywords:  Autophagy; KAT8; MG149; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1038/s41598-024-60602-9
  4. Am J Pathol. 2024 May 16. pii: S0002-9440(24)00174-3. [Epub ahead of print]
    Leucyl-tRNA synthetase contributes to muscle weakness through mTORC1 activation and autophagy suppression in a mouse model of Duchenne Muscular Dystrophy.
    Jae-Sung You, Kate Karaman, Adriana Reyes-Ordoñez, Soohyun Lee, Yongdeok Kim, Rashid Bashir, Jie Chen.
      Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study the DMD mouse model mdx is used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) is found to be hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, is not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) is found to be overexpressed in mdx muscles compared to the wild-type. LeuRS is known to activate mTORC1 in a non-canonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduces mTORC1 activity, restores autophagy, and ameliorates myofiber damage in the mdx muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improves dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncover a non-canonical function of the house-keeping protein LeuRS as a potential therapeutic target in the treatment of DMD.
    Keywords:  Duchenne Muscular Dystrophy; autophagy; leucyl-tRNA synthetase; mTORC1; skeletal muscle weakness
    DOI:  https://doi.org/10.1016/j.ajpath.2024.04.006
  5. Biochim Biophys Acta Mol Cell Res. 2024 May 17. pii: S0167-4889(24)00096-X. [Epub ahead of print] 119753
    Autophagy and metabolic aging: Current understanding and future applications.
    Sana Raza.
      "Metabolic aging" refers to the gradual decline in cellular metabolic function across various tissues due to defective hormonal signaling, impaired nutrient sensing, mitochondrial dysfunction, replicative stress, and cellular senescence. While this process usually corresponds with chronological aging, the recent increase in metabolic diseases and cancers occurring at younger ages in humans suggests the premature onset of cellular fatigue and metabolic aging. Autophagy, a cellular housekeeping process facilitated by lysosomes, plays a crucial role in maintaining tissue rejuvenation and health. However, various environmental toxins, hormones, lifestyle changes, and nutrient imbalances can disrupt autophagy in humans. In this review, we explore the connection between autophagy and cellular metabolism, its regulation by extrinsic factors and its modulation to prevent the early onset of metabolic aging.
    Keywords:  Autophagy; Cellular homeostasis; Disease; Metabolic aging; Metabolism
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119753
  6. Autophagy. 2024 May 18. 1-17
    ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.
    Zhangyang Qi, Weiqi Yang, Baibing Xue, Tingjun Chen, Xianjie Lu, Rong Zhang, Zhichao Li, Xiaoqing Zhao, Yang Zhang, Fabin Han, Xiaohong Kong, Ruikang Liu, Xue Yao, Rui Jia, Shiqing Feng.
      Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.
    Keywords:  Autophagy; ROS; bleomycin; cellular senescence; lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1080/15548627.2024.2353548
  7. Curr Neuropharmacol. 2024 May 17.
    Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.
    Valentina Tedeschi, Silvia Sapienza, Raffaella Ciancio, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.
      Besides controlling several organellar functions, lysosomal channels also guide the catabolic "self-eating" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.
    Keywords:  AD; ALS; HD; LSD; Lysosomal channels; PD; TFEB.; TPC2; TRPML1; autophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/1570159X22666240517101846
  8. Neural Regen Res. 2025 Jan 01. 20(1): 139-158
    The autophagy-lysosome pathway: a potential target in the chemical and gene therapeutic strategies for Parkinson's disease.
    Fengjuan Jiao, Lingyan Meng, Kang Du, Xuezhi Li.
      Parkinson's disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such as α-synuclein in neurons. As one of the major intracellular degradation pathways, the autophagy-lysosome pathway plays an important role in eliminating these proteins. Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance of α-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson's disease. Moreover, multiple genes associated with the pathogenesis of Parkinson's disease are intimately linked to alterations in the autophagy-lysosome pathway. Thus, this pathway appears to be a promising therapeutic target for treatment of Parkinson's disease. In this review, we briefly introduce the machinery of autophagy. Then, we provide a description of the effects of Parkinson's disease-related genes on the autophagy-lysosome pathway. Finally, we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy-lysosome pathway and their applications in Parkinson's disease.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01195
  9. J Cell Biol. 2024 Aug 05. pii: e202309145. [Epub ahead of print]223(8):
    AMPK regulates phagophore-to-autophagosome maturation.
    Carlo Barnaba, David G Broadbent, Emily G Kaminsky, Gloria I Perez, Jens C Schmidt.
      Autophagy is an important metabolic pathway that can non-selectively recycle cellular material or lead to targeted degradation of protein aggregates or damaged organelles. Autophagosome formation starts with autophagy factors accumulating on lipid vesicles containing ATG9. These phagophores attach to donor membranes, expand via ATG2-mediated lipid transfer, capture cargo, and mature into autophagosomes, ultimately fusing with lysosomes for their degradation. Autophagy can be activated by nutrient stress, for example, by a reduction in the cellular levels of amino acids. In contrast, how autophagy is regulated by low cellular ATP levels via the AMP-activated protein kinase (AMPK), an important therapeutic target, is less clear. Using live-cell imaging and an automated image analysis pipeline, we systematically dissect how nutrient starvation regulates autophagosome biogenesis. We demonstrate that glucose starvation downregulates autophagosome maturation by AMPK-mediated inhibition of phagophore tethering to donor membrane. Our results clarify AMPKs regulatory role in autophagy and highlight its potential as a therapeutic target to reduce autophagy.
    DOI:  https://doi.org/10.1083/jcb.202309145
  10. Mol Neurobiol. 2024 May 22.
    Chaperone-Mediated Autophagy in Brain Injury: A Double-Edged Sword with Therapeutic Potentials.
    Huiyi Zhang, Ye Tian, Shuai Ma, Yichen Ji, Zhihang Wang, Peilun Xiao, Ying Xu.
      Autophagy is an intracellular recycling process that maintains cellular homeostasis by degrading excess or defective macromolecules and organelles. Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy in which a substrate containing a KFERQ-like motif is recognized by a chaperone protein, delivered to the lysosomal membrane, and then translocated to the lysosome for degradation with the assistance of lysosomal membrane protein 2A. Normal CMA activity is involved in the regulation of cellular proteostasis, metabolism, differentiation, and survival. CMA dysfunction disturbs cellular homeostasis and directly participates in the pathogenesis of human diseases. Previous investigations on CMA in the central nervous system have primarily focus on neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Recently, mounting evidence suggested that brain injuries involve a wider range of types and severities, making the involvement of CMA in the bidirectional processes of damage and repair even more crucial. In this review, we summarize the basic processes of CMA and its associated regulatory mechanisms and highlight the critical role of CMA in brain injury such as cerebral ischemia, traumatic brain injury, and other specific brain injuries. We also discuss the potential of CMA as a therapeutic target to treat brain injury and provide valuable insights into clinical strategies.
    Keywords:  Brain injury; Brain ischemia; Chaperone-mediated autophagy; Hsc70; LAMP-2A
    DOI:  https://doi.org/10.1007/s12035-024-04230-4
  11. Mol Cell. 2024 May 20. pii: S1097-2765(24)00393-9. [Epub ahead of print]
    mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway.
    Sang Ah Yi, Sara Sepic, Brenda A Schulman, Alban Ordureau, Heeseon An.
      Mammalian target of rapamycin (mTOR) senses changes in nutrient status and stimulates the autophagic process to recycle amino acids. However, the impact of nutrient stress on protein degradation beyond autophagic turnover is incompletely understood. We report that several metabolic enzymes are proteasomal targets regulated by mTOR activity based on comparative proteome degradation analysis. In particular, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) synthase 1 (HMGCS1), the initial enzyme in the mevalonate pathway, exhibits the most significant half-life adaptation. Degradation of HMGCS1 is regulated by the C-terminal to LisH (CTLH) E3 ligase through the Pro/N-degron motif. HMGCS1 is ubiquitylated on two C-terminal lysines during mTORC1 inhibition, and efficient degradation of HMGCS1 in cells requires a muskelin adaptor. Importantly, modulating HMGCS1 abundance has a dose-dependent impact on cell proliferation, which is restored by adding a mevalonate intermediate. Overall, our unbiased degradomics study provides new insights into mTORC1 function in cellular metabolism: mTORC1 regulates the stability of limiting metabolic enzymes through the ubiquitin system.
    Keywords:  CTLH; GID; HMGCS1; degradomics; mTOR; mTORC1; mevalonate pathway; sterol; ubiquitin; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.026
  12. Cell Mol Life Sci. 2024 May 22. 81(1): 227
    Cellular depletion of major cathepsin proteases reveals their concerted activities for lysosomal proteolysis.
    Lisa Gallwitz, Florian Bleibaum, Matthias Voss, Michaela Schweizer, Katharina Spengler, Dominic Winter, Frederic Zöphel, Stephan Müller, Stefan Lichtenthaler, Markus Damme, Paul Saftig.
      Proteins delivered by endocytosis or autophagy to lysosomes are degraded by exo- and endoproteases. In humans 15 lysosomal cathepsins (CTS) act as important physiological regulators. The cysteine proteases CTSB and CTSL and the aspartic protease CTSD are the most abundant and functional important lysosomal proteinases. Whereas their general functions in proteolysis in the lysosome, their individual substrate, cleavage specificity, and their possible sequential action on substrate proteins have been previously studied, their functional redundancy is still poorly understood. To address a possible common role of highly expressed and functional important CTS proteases, we generated CTSB-, CTSD-, CTSL-, and CTSBDL-triple deficient (KO) human neuroblastoma-derived SH-SY5Y cells and CTSB-, CTSD-, CTSL-, CTSZ and CTSBDLZ-quadruple deficient (KO) HeLa cells. These cells with a combined cathepsin deficiency exhibited enlarged lysosomes and accumulated lipofuscin-like storage material. The lack of the three (SH-SY5Y) or four (HeLa) major CTSs caused an impaired autophagic flux and reduced degradation of endocytosed albumin. Proteome analyses of parental and CTS-depleted cells revealed an enrichment of cleaved peptides, lysosome/autophagy-associated proteins, and potentially endocytosed membrane proteins like the amyloid precursor protein (APP), which can be subject to endocytic degradation. Amino- and carboxyterminal APP fragments accumulated in the multiple CTS-deficient cells, suggesting that multiple CTS-mediated cleavage events regularly process APP. In summary, our analyses support the idea that different lysosomal cathepsins act in concert, have at least partially and functionally redundant substrates, regulate protein degradation in autophagy, and control cellular proteostasis, as exemplified by their involvement in the degradation of APP fragments.
    Keywords:  Amyloid precursor protein; Autophagy; Bulk proteolysis; Cathepsins; Lysosome; Protease network; Proteolysis; Proteomics
    DOI:  https://doi.org/10.1007/s00018-024-05274-4
  13. Nat Struct Mol Biol. 2024 May 21.
    eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition.
    Yuichi Shichino, Tomokazu Yamaguchi, Kazuhiro Kashiwagi, Mari Mito, Mari Takahashi, Takuhiro Ito, Nicholas T Ingolia, Keiji Kuba, Shintaro Iwasaki.
      Eukaryotic translation initiation factor (eIF)4A-a DEAD-box RNA-binding protein-plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.
    DOI:  https://doi.org/10.1038/s41594-024-01321-7
  14. Biochim Biophys Acta Mol Basis Dis. 2024 May 21. pii: S0925-4439(24)00245-X. [Epub ahead of print] 167256
    PKD2 regulates autophagy and forms a protein complex with BECN1 at the primary cilium of hypothalamic neuronal cells.
    Camila García-Navarrete, Catalina Kretschmar, Jorge Toledo, Karla Gutiérrez, María Paz Hernández-Cáceres, Mauricio Budini, Valentina Parra, Patricia V Burgos, Sergio Lavandero, Eugenia Morselli, Daniel Peña-Oyarzún, Alfredo Criollo.
      The primary cilium, hereafter cilium, is an antenna-like organelle that modulates intracellular responses, including autophagy, a lysosomal degradation process essential for cell homeostasis. Dysfunction of the cilium is associated with impairment of autophagy and diseases known as "ciliopathies". The discovery of autophagy-related proteins at the base of the cilium suggests its potential role in coordinating autophagy initiation in response to physiopathological stimuli. One of these proteins, beclin-1 (BECN1), it which is necessary for autophagosome biogenesis. Additionally, polycystin-2 (PKD2), a calcium channel enriched at the cilium, is required and sufficient to induce autophagy in renal and cancer cells. We previously demonstrated that PKD2 and BECN1 form a protein complex at the endoplasmic reticulum in non-ciliated cells, where it initiates autophagy, but whether this protein complex is present at the cilium remains unknown. Anorexigenic pro-opiomelanocortin (POMC) neurons are ciliated cells that require autophagy to maintain intracellular homeostasis. POMC neurons are sensitive to metabolic changes, modulating signaling pathways crucial for controlling food intake. Exposure to the saturated fatty acid palmitic acid (PA) reduces ciliogenesis and inhibits autophagy in these cells. Here, we show that PKD2 and BECN1 form a protein complex in N43/5 cells, an in vitro model of POMC neurons, and that both PKD2 and BECN1 locate at the cilium. In addition, our data show that the cilium is required for PKD2-BECN1 protein complex formation and that PA disrupts the PKD2-BECN1 complex, suppressing autophagy. Our findings provide new insights into the mechanisms by which the cilium controls autophagy in hypothalamic neuronal cells.
    Keywords:  Autophagy; Beclin-1; Polycystin-2; Primary cilium
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167256
  15. bioRxiv. 2024 May 09. pii: 2024.05.09.593318. [Epub ahead of print]
    The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux.
    Brian J North, Amelia E Ohnstad, Michael J Ragusa, Christopher J Shoemaker.
      During autophagy, potentially toxic cargo is enveloped by a newly formed autophagosome and trafficked to the lysosome for degradation. Ubiquitinated protein aggregates, a key target for autophagy, are identified by multiple autophagy receptors. NBR1 is an archetypal autophagy receptor and an excellent model for deciphering the role of the multivalent, heterotypic interactions made by cargo-bound receptors. Using NBR1 as a model, we find that three critical binding partners - ATG8-family proteins, FIP200, and TAX1BP1 - each bind to a short linear interaction motif (SLiM) within NBR1. Mutational peptide arrays indicate that these binding events are mediated by distinct overlapping determinants, rather than a single, convergent, SLiM. AlphaFold modeling underlines the need for conformational flexibility within the NBR1 SLiM, as distinct conformations mediate each binding event. To test the extent to which overlapping SLiMs exist beyond NBR1, we performed peptide binding arrays on >100 established LC3-interacting regions (LIRs), revealing that FIP200 and/or TAX1BP1 binding to LIRs is a common phenomenon and suggesting LIRs as protein interaction hotspots. Comparative analysis of phosphomimetic peptides highlights that while FIP200 and Atg8-family binding are generally augmented by phosphorylation, TAX1BP1 binding is nonresponsive, suggesting differential regulation of these binding events. In vivo studies confirm that LIR-mediated interactions with TAX1BP1 enhance NBR1 activity, increasing autophagosomal delivery by leveraging an additional LIR from TAX1BP1. In sum, these results reveal a one-to-many binding modality in NBR1, providing key insights into the cooperative mechanisms among autophagy receptors. Furthermore, these findings underscore the pervasive role of multifunctional SLiMs in autophagy, offering substantial avenues for further exploration into their regulatory functions.
    DOI:  https://doi.org/10.1101/2024.05.09.593318
  16. Biochim Biophys Acta Mol Cell Res. 2024 May 20. pii: S0167-4889(24)00095-8. [Epub ahead of print] 119752
    Mitophagy at the crossroads of cancer development: Exploring the role of mitophagy in tumor progression and therapy resistance.
    K Deepak, Pritam Kumar Roy, Chandan Kanta Das, Budhaditya Mukherjee, Mahitosh Mandal.
      Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future.
    Keywords:  Anticancer therapeutics; Drug resistance; Metabolic rewiring; Mitophagy; Pathway mechanism; Stemness maintenance
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119752
  17. Integr Comp Biol. 2024 May 17. pii: icae042. [Epub ahead of print]
    Beclin-mediated Autophagy Drives Dorsal Longitudinal Flight Muscle Histolysis in the Variable Field Cricket, Gryllus lineaticeps.
    Tomás Diaz, Lisa A Treidel, Michael A Menze, Caroline M Williams, Jacqueline E Lebenzon.
      Flight muscle histolysis is a widespread strategy used by insects to break down functional flight muscle and modulate the energetic costs associated with flight muscle use and maintenance. The variable field cricket, Gryllus lineaticeps, undergoes histolysis during their transition between dispersal flight and reproduction. Despite the importance of histolysis on insect reproduction and fitness, the molecular mechanisms driving this flight muscle breakdown are not well understood. Here, we show that beclin-mediated autophagy, a conserved lysosomal-dependent degradation process, drives breakdown of dorsal longitudinal flight muscle in female flight capable G. lineaticeps. We found that female G. lineaticeps activate autophagy in their dorsal longitudinal flight muscle (DLM), but to a greater extent than the neighboring dorsoventral flight muscle (DVM) during histolysis. RNA interference knockdown of beclin, a gene which encodes a critical autophagy initiation protein, delayed DLM histolysis, but did not affect DVM histolysis. This suggests that crickets selectively activate autophagy to break down the DLMs, while maintaining DVM function for other fitness-relevant activities such as walking. Overall, we confirmed that autophagy is a critical pathway used to remodel flight muscle cells during flight muscle histolysis, providing novel insights into the mechanisms underlying a major life history transition between dispersal and reproduction.
    DOI:  https://doi.org/10.1093/icb/icae042
  18. Cell Rep. 2024 May 17. pii: S2211-1247(24)00583-7. [Epub ahead of print]43(5): 114255
    Upregulation of neuronal ER-phagy improves organismal fitness and alleviates APP toxicity.
    Wenqing Mou, Yinglu Tang, Yunpeng Huang, Zhihao Wu, Yixian Cui.
      ER-phagy, a selective autophagy targeting the endoplasmic reticulum (ER) for lysosomal degradation through cargo receptors, plays a critical role in ER quality control and is linked to various diseases. However, its physiological and pathological roles remain largely unclear due to a lack of animal model studies. This study establishes Drosophila as an in vivo ER-phagy model. Starvation triggers ER-phagy across multiple fly tissues. Disturbing ER-phagy by either globally upregulating or downregulating ER-phagy receptors, Atl or Rtnl1, harms the fly. Notably, moderate upregulation of ER-phagy in fly brains by overexpressing Atl or Rtnl1 significantly attenuates age-associated neurodegenerations. Furthermore, in a Drosophila model of Alzheimer's disease expressing human amyloid precursor protein (APP), impaired ER-phagy is observed. Enhancing ER-phagy in the APP-expressing fly brain facilitates APP degradation, significantly alleviating disease symptoms. Therefore, our findings suggest that modulating ER-phagy may offer a therapeutic strategy to treat aging and diseases associated with ER protein aggregation.
    Keywords:  APP; Atg8a; Atl; CP: Cell biology; CP: Molecular biology; ER-phagy; Rtnl1; aging; cargo receptor; macro-autophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114255
  19. Plant Physiol Biochem. 2024 May 19. pii: S0981-9428(24)00368-1. [Epub ahead of print]212 108700
    A synchronized symphony: Intersecting roles of ubiquitin proteasome system and autophagy in cellular degradation.
    Isha Sharma, Ashwini Talakayala, Manish Tiwari, Sarath Asinti, P B Kirti.
      Eukaryotic cells have evolved dynamic quality control pathways and recycling mechanisms for cellular homeostasis. We discuss here, the two major systems for quality control, the ubiquitin-proteasome system (UPS) and autophagy that regulate cellular protein and organelle turnover and ensure efficient nutrient management, cellular integrity and long-term wellbeing of the plant. Both the pathways rely on ubiquitination signal to identify the targets for proteasomal and autophagic degradation, yet they use distinct degradation machinery to process these cargoes. Nonetheless, both UPS and autophagy operate together as an interrelated quality control mechanism where they communicate with each other at multiple nodes to coordinate and/or compensate the recycling mechanism particularly under development and environmental cues. Here, we provide an update on the cellular machinery of autophagy and UPS, unravel the nodes of their crosstalk and particularly highlight the factors responsible for their differential deployment towards protein, macromolecular complexes and organelles.
    DOI:  https://doi.org/10.1016/j.plaphy.2024.108700
  20. Hepatol Commun. 2024 Jun 01. pii: e0446. [Epub ahead of print]8(6):
    Ethanol disrupts hepatocellular lipophagy by altering Rab5-centric LD-lysosome trafficking.
    Micah B Schott, Cody N Rozeveld, Saumya Bhatt, Bridget Crossman, Eugene W Krueger, Shaun G Weller, Karuna Rasineni, Carol A Casey, Mark A McNiven.
       BACKGROUND: Previous reports suggest that lipid droplets (LDs) in the hepatocyte can be catabolized by a direct engulfment from nearby endolysosomes (microlipophagy). Further, it is likely that this process is compromised by chronic ethanol (EtOH) exposure leading to hepatic steatosis. This study investigates the hepatocellular machinery supporting microlipophagy and EtOH-induced alterations in this process with a focus on the small, endosome-associated, GTPase Rab5.
    METHODS AND RESULTS: Here we report that this small Ras-related GTPase is a resident component of LDs, and its activity is important for hepatocellular LD-lysosome proximity and physical interactions. We find that Rab5 siRNA knockdown causes an accumulation of LDs in hepatocytes by inhibiting lysosome dependent LD catabolism. Importantly, Rab5 appears to support this process by mediating the recruitment of early endosomal and or multivesicular body compartments to the LD surface before lysosome fusion. Interestingly, while wild-type or a constituently active GTPase form (Q79L) of Rab5 supports LD-lysosome transport, this process is markedly reduced in cells expressing a GTPase dead (S34N) Rab5 protein or in hepatocytes exposed to chronic EtOH.
    CONCLUSIONS: These findings support the novel premise of an early endosomal/multivesicular body intermediate compartment on the LD surface that provides a "docking" site for lysosomal trafficking, not unlike the process that occurs during the hepatocellular degradation of endocytosed ligands that is also known to be compromised by EtOH exposure.
    DOI:  https://doi.org/10.1097/HC9.0000000000000446
  21. Am J Physiol Cell Physiol. 2024 May 20.
    mTORC1 and BMP-Smad1/5 Regulation of Serum-Stimulated Myotube Hypertrophy: A Role for Autophagy.
    Quan Zhang, Jessica L Halle, Brittany R Counts, James A Carson.
      Protein synthesis regulation is critical for skeletal muscle hypertrophy; yet, other established cellular processes are necessary for growth-related cellular remodeling. Autophagy has a well-acknowledged role in muscle quality control, but evidence for its role in myofiber hypertrophy remains equivocal. Both mTORC1 and BMP-Smad1/5 signaling are reported regulators of myofiber hypertrophy; however, gaps remain in our understanding of how this regulation is integrated with the growth processes and autophagy regulation. Therefore, we investigated the mTORC1 and Smad1/5 regulation of protein synthesis and autophagy flux during serum-stimulated myotube growth. Chronic serum stimulation experiments were performed on day-5 differentiated C2C12 myotubes incubated in differentiation media (2%HS) or growth media (5%FBS) for 48 hours. Rapamycin or LDN193189 were dosed for 48 hours to inhibit mTORC1 and BMP-Smad1/5 signaling, respectively. Acute serum stimulation was examined in day-7 differentiated myotubes. Protein synthesis was measured by puromycin incorporation. Bafilomycin A1 and immunoblotting for LC3B were used to assess autophagy flux. Chronic serum stimulation increased myotube diameter 22%, total protein 21%, total RNA 100%, Smad1/5 phosphorylation 404%, and suppressed autophagy flux. Rapamycin, but not LDN193189, blocked serum-induced myotube hypertrophy and the increase in total RNA. Acute serum stimulation increased protein synthesis 111%, Smad1/5 phosphorylation 559%, rpS6 phosphorylation 117%, and suppressed autophagy flux. Rapamycin increased autophagy flux during acute serum stimulation. These results provide evidence for mTORC1, but not BMP-Smad1/5 signaling, being required for serum-induced myotube hypertrophy and autophagy flux by measuring LC3BII/I expression. Further investigation is warranted to examine the role of autophagy flux in myotube hypertrophy.
    Keywords:  C2C12 myotubes; cell growth; protein synthesis; rapamycin
    DOI:  https://doi.org/10.1152/ajpcell.00237.2024
  22. Biomed Pharmacother. 2024 May 21. pii: S0753-3322(24)00674-7. [Epub ahead of print]175 116790
    Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy.
    Jie Li, Yingying Xie, Shuwen Zheng, Haoming He, Zhe Wang, Xuexi Li, Siqi Jiao, Dong Liu, Furong Yang, Hailing Zhao, Ping Li, Yihong Sun.
      Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.
    Keywords:  Autophagy; Chemical drugs; Diabetic cardiomyopathy; Molecular mechanisms; Natural product; Pharmacotherapy
    DOI:  https://doi.org/10.1016/j.biopha.2024.116790
  23. J Extracell Vesicles. 2024 May;13(5): e12448
    Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model.
    Suraj Singh Rawat, Anand Kumar Keshri, Naina Arora, Rimanpreet Kaur, Amit Mishra, Rajiv Kumar, Amit Prasad.
      The excretory-secretory proteome plays a pivotal role in both intercellular communication during disease progression and immune escape mechanisms of various pathogens including cestode parasites like Taenia solium. The cysticerci of T. solium causes infection in the central nervous system known as neurocysticercosis (NCC), which affects a significant population in developing countries. Extracellular vesicles (EVs) are 30-150-nm-sized particles and constitute a significant part of the secretome. However, the role of EV in NCC pathogenesis remains undetermined. Here, for the first time, we report that EV from T. solium larvae is abundant in metabolites that can negatively regulate PI3K/AKT pathway, efficiently internalized by macrophages to induce AKT and mTOR degradation through auto-lysosomal route with a prominent increase in the ubiquitination of both proteins. This results in less ROS production and diminished bacterial killing capability among EV-treated macrophages. Due to this, both macro-autophagy and caspase-linked apoptosis are upregulated, with a reduction of the autophagy substrate sequestome 1. In summary, we report that T. solium EV from viable cysts attenuates the AKT-mTOR pathway thereby promoting apoptosis in macrophages, and this may exert immunosuppression during an early viable stage of the parasite in NCC, which is primarily asymptomatic. Further investigation on EV-mediated immune suppression revealed that the EV can protect the mice from DSS-induced colitis and improve colon architecture. These findings shed light on the previously unknown role of T. solium EV and the therapeutic role of their immune suppression potential.
    Keywords:  AKT; EVs; Taenia solium; apoptosis; autophagy; neurocysticercosis
    DOI:  https://doi.org/10.1002/jev2.12448
  24. Naunyn Schmiedebergs Arch Pharmacol. 2024 May 18.
    Targeting the autophagy-miRNA axis in prostate cancer: toward novel diagnostic and therapeutic strategies.
    Rahamat Unissa Syed, Maali D Alshammari, Humera Banu, Weam M A Khojali, Mohammed Jafar, Potnuri Nagaraju, Alia Alshammari.
      Since prostate cancer is one of the leading causes of cancer-related death, a better understanding of the molecular pathways guiding its development is imperative. A key factor in prostate cancer is autophagy, a cellular mechanism that affects both cell survival and death. Autophagy is essential in maintaining cellular homeostasis. Autophagy is a physiological mechanism wherein redundant or malfunctioning cellular constituents are broken down and recycled. It is essential for preserving cellular homeostasis and is implicated in several physiological and pathological conditions, including cancer. Autophagy has been linked to metastasis, tumor development, and treatment resistance in prostate cancer. The deregulation of miRNAs related to autophagy appears to be a crucial element in the etiology of prostate cancer. These miRNAs influence the destiny of cancer cells by finely regulating autophagic mechanisms. Numerous investigations have emphasized the dual function of specific miRNAs in prostate cancer, which alter autophagy-related pathways to function as either tumor suppressors or oncogenes. Notably, miRNAs have been linked to the control of autophagy and the proliferation, apoptosis, and migration of prostate cancer cells. To create customized therapy approaches, it is imperative to comprehend the dynamic interplay between autophagy and miRNAs in prostate cancer. The identification of key miRNAs provides potential diagnostic and prognostic markers. Unraveling the complex network of lncRNAs, like PCA3, also expands the repertoire of molecular targets for therapeutic interventions. This review explores the intricate interplay between autophagy and miRNAs in prostate cancer, focusing on their regulatory roles in cellular processes ranging from survival to programmed cell death.
    Keywords:  Autophagy; Cell survival; Molecular regulation; Programmed cell death; Prostate cancer; Therapeutic targets; microRNAs
    DOI:  https://doi.org/10.1007/s00210-024-03153-0
  25. bioRxiv. 2024 May 07. pii: 2024.05.06.592795. [Epub ahead of print]
    Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
    Kylie R VanDerMolen, Martin A Newman, Peter C Breen, Laura A Huff, Robert H Dowen.
      Organisms must appropriately allocate energetic resources between essential cellular processes to maintain homeostasis and in turn, maximize fitness. The nutritional and homeostatic regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern cellular metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in C. elegans . We find that expression of two Hh ligands, GRD-3 and GRD-4, is controlled by the LIN-29/EGR transcription factor in the hypodermis, where the Hh secretion factor CHE-14/Dispatched also facilitates non-cell autonomous Hh signaling. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor, TRA-1/GLI, but rather through non-canonical signaling that engages mTOR Complex 2 (mTORC2) in the intestine. Hh mutants display impaired lipid homeostasis, including reduced lipoprotein synthesis and fat accumulation, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we found that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation and that both pathways act together to modulate of lipid homeostasis. Our findings show a non-canonical role for Hedgehog signaling in lipid metabolism via regulation of core homeostatic pathways and reveal a new mechanism by which developmental timing events govern metabolic decisions.
    DOI:  https://doi.org/10.1101/2024.05.06.592795
  26. Exp Brain Res. 2024 May 24.
    Traumatic brain injury heterogeneity affects cell death and autophagy.
    Brandon Z McDonald, Aria W Tarudji, Haipeng Zhang, Sangjin Ryu, Kent M Eskridge, Forrest M Kievit.
      Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.
    Keywords:  Autophagy; Cell death; Concussion/mild TBI; Secondary injury
    DOI:  https://doi.org/10.1007/s00221-024-06856-1
  27. Autophagy. 2024 May 18.
    VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
    Zhifeng Wang, Shuhui Xiong, Zhaoyi Wu, Xingde Wang, Yamin Gong, Wei-Guo Zhu, Xingzhi Xu.
      Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases.
    Keywords:  BECN1/beclin 1; PtdIns3K complex; UFL1; Ufmylation; Vcp/p97
    DOI:  https://doi.org/10.1080/15548627.2024.2356488
  28. Neural Regen Res. 2025 Jan 01. 20(1): 6-20
    Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases.
    Xiu-Yun Zhao, De-En Xu, Ming-Lei Wu, Ji-Chuan Liu, Zi-Ling Shi, Quan-Hong Ma.
      The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-00995
  29. CNS Neurosci Ther. 2024 May;30(5): e14763
    Autophagy-associated non-coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis.
    Md Sadique Hussain, Ehssan Moglad, Muhammad Afzal, Shilpa Sharma, Gaurav Gupta, G V Sivaprasad, Mahamedha Deorari, Waleed Hassan Almalki, Imran Kazmi, Sami I Alzarea, Moyad Shahwan, Kumud Pant, Haider Ali, Sachin Kumar Singh, Kamal Dua, Vetriselvan Subramaniyan.
       BACKGROUND: Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The precise etiology of PD remains unclear, but emerging evidence suggests a significant role for disrupted autophagy-a crucial cellular process for maintaining protein and organelle integrity.
    METHODS: This review focuses on the role of non-coding RNAs (ncRNAs) in modulating autophagy in PD. We conducted a comprehensive review of recent studies to explore how ncRNAs influence autophagy and contribute to PD pathophysiology. Special attention was given to the examination of ncRNAs' regulatory impacts in various PD models and patient samples.
    RESULTS: Findings reveal that ncRNAs are pivotal in regulating key processes associated with PD progression, including autophagy, α-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation. Dysregulation of specific ncRNAs appears to be closely linked to these pathogenic processes.
    CONCLUSION: ncRNAs hold significant therapeutic potential for addressing autophagy-related mechanisms in PD. The review highlights innovative therapeutic strategies targeting autophagy-related ncRNAs and discusses the challenges and prospective directions for developing ncRNA-based therapies in clinical practice. The insights from this study underline the importance of ncRNAs in the molecular landscape of PD and their potential in novel treatment approaches.
    Keywords:  Parkinson's disease; autophagy; ncRNA; neuroinflammation; α‐synuclein
    DOI:  https://doi.org/10.1111/cns.14763
  30. Cell Mol Life Sci. 2024 May 20. 81(1): 223
    PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.
    Lene Clausen, Justyna Okarmus, Vasileios Voutsinos, Morten Meyer, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.
      Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.
    Keywords:  AR-JP; DMS; MAVE; Mitochondria; PARK2; PRKN; Parkinson’s disease; Proteasome; Protein degradation; Protein folding; Protein quality control; Protein stability; Ubiquitin; VUS
    DOI:  https://doi.org/10.1007/s00018-024-05262-8
  31. Biomed Pharmacother. 2024 May 17. pii: S0753-3322(24)00629-2. [Epub ahead of print]175 116745
    Propolis as an autophagy modulator in relation to its roles in redox balance and inflammation regulation.
    R Lesmana, S Tandean, A Christoper, A A Suwantika, N Wathoni, R Abdulah, J Fearnley, V Bankova, F Zulhendri.
      Autophagy is a degradation process that is evolutionarily conserved and is essential in maintaining cellular and physiological homeostasis through lysosomal removal and elimination of damaged peptides, proteins and cellular organelles. The dysregulation of autophagy is implicated in various diseases and disorders, including cancers, infection-related, and metabolic syndrome-related diseases. Propolis has been demonstrated in various studies including many human clinical trials to have antimicrobial, antioxidant, anti-inflammatory, immune-modulator, neuro-protective, and anti-cancer. Nevertheless, the autophagy modulation properties of propolis have not been extensively studied and explored. The role of propolis and its bioactive compounds in modulating cellular autophagy is possibly due to their dual role in redox balance and inflammation. The present review attempts to discuss the activities of propolis as an autophagy modulator in biological models in relation to various diseases/disorders which has implications in the development of propolis-based nutraceuticals, functional foods, and complementary therapies.
    Keywords:  Anti-inflammatory; Antioxidant; Autophagy; Functional food; Nutraceutical; Pro-oxidant; Propolis
    DOI:  https://doi.org/10.1016/j.biopha.2024.116745
  32. Autophagy. 2024 May 18. 1-3
    Gonococcal OMVs induce epithelial cell mitophagy in a dual PorB-dependent manner to enhance intracellular survival.
    Shuai Gao, Stijn van der Veen.
      Outer membrane vesicles (OMVs) are nanometer-sized membrane blebs secreted by all Gram-negative bacteria to facilitate bacterial communication and modulate the external environment, including in the context of host-microbe interactions. Neisseria gonorrhoeae releases OMVs during interactions with epithelial cells; however, beneficial functional activities for these OMVs have not yet been demonstrated. Our recent study shows that gonococcal OMVs are endocytosed by epithelial cells and subsequently induce mitophagy through a dual PorB-dependent mechanism. PorB is the major gonococcal outer membrane porin protein, which is able to translocate to mitochondria and dissipate the mitochondrial membrane potential, leading to the initiation of a conventional mitophagy mechanism that is dependent on PINK1 and the receptor proteins OPTN or CALCOCO2/NDP52. A second SQSTM1/p62-dependent mitophagy pathway results from direct K63-linked polyubiquitination of PorB lysine residue 171 by the E3 ubiquitin ligase RNF213. Induction of mitophagy favors intracellular gonococcal survival, because it reduces the release of bactericidal mitochondrial reactive oxygen species. These findings highlight a sophisticated bimodal PorB-dependent mechanism by which gonococcal OMVs modulate the intracellular environment to enhance survival in this hostile niche.
    Keywords:  Mitophagy; Neisseria gonorrhoeae; PorB; RNF213; outer membrane vesicles; polyubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2356486
  33. Biophys Rep. 2024 Apr 30. 10(2): 111-120
    Exploring lysosomal biology: current approaches and methods.
    Qiuyuan Yin, Chonglin Yang.
      Lysosomes are the degradation centers and signaling hubs in the cell. Lysosomes undergo adaptation to maintain cell homeostasis in response to a wide variety of cues. Dysfunction of lysosomes leads to aging and severe diseases including lysosomal storage diseases (LSDs), neurodegenerative disorders, and cancer. To understand the complexity of lysosome biology, many research approaches and tools have been developed to investigate lysosomal functions and regulatory mechanisms in diverse experimental systems. This review summarizes the current approaches and tools adopted for studying lysosomes, and aims to provide a methodological overview of lysosomal research and related fields.
    Keywords:  C. elegans; Cultured cell; Lysosome; Method; Mice
    DOI:  https://doi.org/10.52601/bpr.2023.230028
  34. Reprod Biol. 2024 May 21. pii: S1642-431X(24)00040-8. [Epub ahead of print]24(2): 100894
    Research progress on the role of autophagy in the development of varicocele.
    Yunqing Li, Yulan Zhou, Tianzhong Ma, Jiaze Dai, Hongbo Li, Qingjun Pan, Wenying Luo.
      Varicocele (VC) is a common cause of infertility in men. Pathophysiological changes caused by VC, such as testicular hypoxia, high temperatures, oxidative stress, abnormal reproductive hormones, and Cd accumulation, can induce autophagy, thus affecting the reproductive function in patients with this condition. Autophagy regulators can be classified as activators or inhibitors. Autophagy activators upregulate autophagy, reduce the damage to the testis and epididymis, inhibit spermatogenic cell apoptosis, and protect fertility. In contrast, autophagy inhibitors block autophagy and aggravate the damage to the reproductive functions. Therefore, elucidating the role of autophagy in the occurrence, development, and regulation of VC may provide additional therapeutic options for men with infertility and VC. In this review, we briefly describe the progress made in autophagy research in the context of VC.
    Keywords:  Autophagy; Infertility; Pathophysiology; Research progress; Varicocele
    DOI:  https://doi.org/10.1016/j.repbio.2024.100894
  35. Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2315690121
    Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes.
    Kevin Rose, Tyler Jepson, Sankalp Shukla, Alex Maya-Romero, Martin Kampmann, Ke Xu, James H Hurley.
      The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer's disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.
    Keywords:  Alzheimer’s disease; ESCRT; STORM; astrocyte; lysosome
    DOI:  https://doi.org/10.1073/pnas.2315690121
  36. Autophagy. 2024 May 18. 1-8
    Accurate automated segmentation of autophagic bodies in yeast vacuoles using cellpose 2.0.
    Emily C Marron, Jonathan Backues, Andrew M Ross, Steven K Backues.
      Segmenting autophagic bodies in yeast TEM images is a key technique for measuring changes in autophagosome size and number in order to better understand macroautophagy/autophagy. Manual segmentation of these images can be very time consuming, particularly because hundreds of images are needed for accurate measurements. Here we describe a validated Cellpose 2.0 model that can segment these images with accuracy comparable to that of human experts. This model can be used for fully automated segmentation, eliminating the need for manual body outlining, or for model-assisted segmentation, which allows human oversight but is still five times as fast as the current manual method. The model is specific to segmentation of autophagic bodies in yeast TEM images, but researchers working in other systems can use a similar process to generate their own Cellpose 2.0 models to attempt automated segmentations. Our model and instructions for its use are presented here for the autophagy community.Abbreviations: AB, autophagic body; AvP, average precision; GUI, graphical user interface; IoU, intersection over union; MVB, multivesicular body; ROI, region of interest; TEM, transmission electron microscopy; WT,wild type.
    Keywords:  Automated labeling; autophagy; computer vision; electron microscopy; image analysis; machine learning
    DOI:  https://doi.org/10.1080/15548627.2024.2353458
  37. Theriogenology. 2024 May 09. pii: S0093-691X(24)00177-8. [Epub ahead of print]224 119-133
    Lysine-specific demethylase 1 (LSD1) participate in porcine early embryonic development by regulating cell autophagy and apoptosis through the mTOR signaling pathway.
    Jiajia Qi, Shaoxuan Zhang, Hexuan Qu, Yanqiu Wang, Yanwei Dong, Huakai Wei, Yu Wang, Boxing Sun, Hao Jiang, Jiabao Zhang, Shuang Liang.
      Lysine-specific demethylase 1 (LSD1) stands as the pioneering histone demethylase uncovered, proficient in demethylating H3K4me1/2 and H3K9me1/2, thereby governing transcription and participating in cell apoptosis, proliferation, or differentiation. Nevertheless, the complete understanding of LSD1 during porcine early embryonic development and the underlying molecular mechanism remains unclear. Thus, we investigated the mechanism by which LSD1 plays a regulatory role in porcine early embryos. This study revealed that LSD1 inhibition resulted in parthenogenetic activation (PA) and in vitro fertilization (IVF) embryo arrested the development, and decreased blastocyst quality. Meanwhile, H3K4me1/2 and H3K9me1/2 methylase activity was increased at the 4-cell embryo stage. RNA-seq results revealed that autophagy related biological processes were highly enriched through GO and KEGG pathway analyses when LSD1 inhibition. Further studies showed that LSD1 depletion in porcine early embryos resulted in low mTOR and p-mTOR levels and high autophagy and apoptosis levels. The LSD1 deletion-induced increases in autophagy and apoptosis could be reversed by addition of mTOR activators. We further demonstrated that LSD1 inhibition induced mitochondrial dysfunction and mitophagy. In summary, our research results indicate that LSD1 may regulate autophagy and apoptosis through the mTOR pathway and affect early embryonic development of pigs.
    Keywords:  Autophagy; LSD1; Porcine early embryonic development
    DOI:  https://doi.org/10.1016/j.theriogenology.2024.05.010
  38. Curr Med Chem. 2024 May 22.
    Autophagy-related ncRNAs: Regulatory Roles and Potential Therapeutic Effects in Digestive System Neoplasms.
    Liushan Wei, Shijie Wu, Xiaoyong Lei, Xiaoyan Yang.
      Among all cancers in the world, the incidence rate of digestive system neoplasms accounts for about 25%, while the mortality rate accounts for about 35%. Difficulty in detecting early digestive system cancers and its poor prognosis are the two main reasons for the high mortality rate. Understanding of the basic cellular processes is of significance and autophagy is one of these processes. Considering the importance of autophagy in pathological state functions, the mechanism of autophagy was initially carried out. In this paper, we will review the molecular mechanisms and biological functions of autophagy-associated ncRNAs in different types of digestive system cancers. Autophagy is a process that supports nutrient cycling and metabolic adaptation accomplished through multi-step lysosomal degradation. It has been suggested that autophagy has a dual role in cancer, which limits tumorigenesis in some stages but promotes tumor progression in others. NcRNAs are also shown to modulate cellular autophagy and thus affect the development of digestive system neoplasms. More and more evidence suggests that the regulation of autophagy by ncRNAs plays a complex role in cancer initiation, progression, metastasis, recurrence, and treatment resistance, which might make ncRNAs therapeutic targets for digestive system neoplasms. While miRNAs participate mainly in post-transcriptional regulation, lncRNAs, and circRNAs usually serve as molecular sponges that have more diverse regulatory functions.
    Keywords:  Autophagy; circRNA; digestive system neoplasms.; lncRNA; miRNA; molecular sponge
    DOI:  https://doi.org/10.2174/0109298673286057240311073143
  39. Metab Brain Dis. 2024 May 21.
    High salt diet induces cognitive impairment and is linked to the activation of IGF1R/mTOR/p70S6K signaling.
    Shu Liu, Xu Yang, Minghao Yuan, Shengyuan Wang, Haixia Fan, Qian Zou, Yinshuang Pu, Zhiyou Cai.
      A high-salt diet (HSD) has been associated with various health issues, including hypertension and cardiovascular diseases. However, recent studies have revealed a potential link between high salt intake and cognitive impairment. This study aims to investigate the effects of high salt intake on autophagy, tau protein hyperphosphorylation, and synaptic function and their potential associations with cognitive impairment. To explore these mechanisms, 8-month-old male C57BL/6 mice were fed either a normal diet (0.4% NaCl) or an HSD (8% NaCl) for 3 months, and Neuro-2a cells were incubated with normal medium or NaCl medium (80 mM). Behavioral tests revealed learning and memory deficits in mice fed the HSD. We further discovered that the HSD decreased autophagy, as indicated by diminished levels of the autophagy-associated proteins Beclin-1 and LC3, along with an elevated p62 protein level. HSD feeding significantly decreased insulin-like growth factor-1 receptor (IGF1R) expression in the brain of C57BL/6 mice and activated mechanistic target of rapamycin (mTOR) signaling. In addition, the HSD reduced synaptophysin and postsynaptic density protein 95 (PSD95) expression in the hippocampus and caused synaptic loss in mice. We also found amyloid β accumulation and hyperphosphorylation of tau protein at different loci both in vivo and in vitro. Overall, this study highlights the clinical significance of understanding the impact of an HSD on cognitive function. By targeting the IGF1R/mTOR/p70S6K pathway or promoting autophagy, it may be possible to mitigate the negative effects of high salt intake on cognitive function.
    Keywords:  Autophagy; Cognitive impairment; High salt diet; IGF1R; Tau hyperphosphorylation; mTOR pathway
    DOI:  https://doi.org/10.1007/s11011-024-01358-z
  40. Autophagy. 2024 May 18.
    Bunyavirus SFTSV NSs utilizes autophagy to escape the antiviral innate immune response.
    Ze-Min Li, Shu-Hui Duan, Tian-Mei Yu, Bang Li, Wen-Kang Zhang, Chuan-Min Zhou, Xue-Jie Yu.
      Severe fever with thrombocytopenia syndrome virus (SFTSV) nonstructural protein (NSs) is an important viral virulence factor that sequesters multiple antiviral proteins into inclusion bodies to escape the antiviral innate immune response. However, the mechanism of the NSs restricting host innate immunity remains largely elusive. Here, we found that the NSs induced complete macroautophagy/autophagy by interacting with the CCD domain of BECN1, thereby promoting the formation of a BECN1-dependent autophagy initiation complex. Importantly, our data showed that the NSs sequestered antiviral proteins such as TBK1 into autophagic vesicles, and therefore promoted the degradation of TBK1 and other antiviral proteins. In addition, the 8A mutant of NSs reduced the induction of BECN1-dependent autophagy flux and degradation of antiviral immune proteins. In conclusion, our results indicated that SFTSV NSs sequesters antiviral proteins into autophagic vesicles for degradation and to escape antiviral immune responses.
    Keywords:  Autophagy; SFTSV; TBK1; immune escape; inclusion bodies
    DOI:  https://doi.org/10.1080/15548627.2024.2356505
  41. EMBO Rep. 2024 May 21.
    ER-to-lysosome-associated degradation acts as failsafe mechanism upon ERAD dysfunction.
    Elisa Fasana, Ilaria Fregno, Carmela Galli, Tatiana Soldà, Maurizio Molinari.
      The endoplasmic reticulum (ER) produces proteins destined to organelles of the endocytic and secretory pathways, the plasma membrane, and the extracellular space. While native proteins are transported to their intra- or extracellular site of activity, folding-defective polypeptides are retro-translocated across the ER membrane into the cytoplasm, poly-ubiquitylated and degraded by 26 S proteasomes in a process called ER-associated degradation (ERAD). Large misfolded polypeptides, such as polymers of alpha1 antitrypsin Z (ATZ) or mutant procollagens, fail to be dislocated across the ER membrane and instead enter ER-to-lysosome-associated degradation (ERLAD) pathways. Here, we show that pharmacological or genetic inhibition of ERAD components, such as the α1,2-mannosidase EDEM1 or the OS9 ERAD lectins triggers the delivery of the canonical ERAD clients Null Hong Kong (NHK) and BACE457Δ to degradative endolysosomes under control of the ER-phagy receptor FAM134B and the LC3 lipidation machinery. Our results reveal that ERAD dysfunction is compensated by the activation of FAM134B-driven ERLAD pathways that ensure efficient lysosomal clearance of orphan ERAD clients.
    Keywords:  ER-associated Degradation (ERAD); ER-phagy; ER-to-Lysosome-associated Degradation (ERLAD); Endoplasmic Reticulum (ER); Protein Quality Control
    DOI:  https://doi.org/10.1038/s44319-024-00165-y
  42. eGastroenterology. 2024 Apr;pii: e100057. [Epub ahead of print]2(2):
    Recent insights about autophagy in pancreatitis.
    Wen-Xing Ding, Xiaowen Ma, Sydney Kim, Shaogui Wang, Hong-Min Ni.
      Acute pancreatitis is a common inflammatory gastrointestinal disease without any successful treatment. Pancreatic exocrine acinar cells have high rates of protein synthesis to produce and secrete large amounts of digestive enzymes. When the regulation of organelle and protein homeostasis is disrupted, it can lead to endoplasmic reticulum (ER) stress, damage to the mitochondria and improper intracellular trypsinogen activation, ultimately resulting in acinar cell damage and the onset of pancreatitis. To balance the homeostasis of organelles and adapt to protect themselves from organelle stress, cells use protective mechanisms such as autophagy. In the mouse pancreas, defective basal autophagy disrupts ER homoeostasis, leading to ER stress and trypsinogen activation, resulting in spontaneous pancreatitis. In this review, we discuss the regulation of autophagy and its physiological role in maintaining acinar cell homeostasis and function. We also summarise the current understanding of the mechanisms and the role of defective autophagy at multiple stages in experimental pancreatitis induced by cerulein or alcohol.
    DOI:  https://doi.org/10.1136/egastro-2023-100057
  43. Res Sq. 2024 May 10. pii: rs.3.rs-4356493. [Epub ahead of print]
    Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.
    Nicholas Hertz, Randall Chin, Rishi Rakhit, Dara Ditsworth, Chengzhong Wang, Johan Bartholomeus, Song Liu, Akash Mody, Alex Laihsu, Andrea Eastes, Chao Tai, Roy Kim, Jessica Li, Saurabh Khasnavis, Victoria Rafalski, Donald Heerendeen, Virginia Garda, Jennie Phung, Daniel de Roulet, Alban Ordureau, J Wade Harper, Shawn Johnstone, Jan Stöhr.
      PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.
    DOI:  https://doi.org/10.21203/rs.3.rs-4356493/v1
  44. World J Gastroenterol. 2024 May 14. 30(18): 2391-2396
    Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?
    Michele Barone.
      This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.
    Keywords:  Autophagy; Hepatic stellate cells; Hepatocellular carcinoma; Liver fibrosis; Renin-angiotensin system
    DOI:  https://doi.org/10.3748/wjg.v30.i18.2391
  45. Int J Mol Sci. 2024 May 17. pii: 5478. [Epub ahead of print]25(10):
    Inhibition of ERK1/2 or CRMP2 Disrupts Alcohol Memory Reconsolidation and Prevents Relapse in Rats.
    Nofar Rahamim, Mirit Liran, Coral Aronovici, Hila Flumin, Tamar Gordon, Nataly Urshansky, Segev Barak.
      Relapse to alcohol abuse, often caused by cue-induced alcohol craving, is a major challenge in alcohol addiction treatment. Therefore, disrupting the cue-alcohol memories can suppress relapse. Upon retrieval, memories transiently destabilize before they reconsolidate in a process that requires protein synthesis. Evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), governing the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase 1/2 (ERK1/2), in the reconsolidation process in a rat (Wistar) model of alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, while the PI3K-AKT pathway remained unaffected. Importantly, ERK1/2 inhibition after alcohol memory retrieval impaired alcohol-memory reconsolidation and led to long-lasting relapse suppression. Attenuation of relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2)-a translational product of mTORC1. Together, our findings indicate the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, with their inhibition as potential treatment targets for relapse prevention.
    Keywords:  CRMP2; ERK1/2; addiction; alcohol; memory reconsolidation; signaling
    DOI:  https://doi.org/10.3390/ijms25105478
  46. Neurobiol Dis. 2024 May 17. pii: S0969-9961(24)00135-9. [Epub ahead of print]197 106536
    Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model.
    Maria Marchese, Sara Bernardi, Asahi Ogi, Rosario Licitra, Giada Silvi, Serena Mero, Daniele Galatolo, Nicola Gammaldi, Stefano Doccini, Gian Michele Ratto, Simona Rapposelli, Stephan C F Neuhauss, Jingjing Zang, Silvia Rocchiccioli, Elena Michelucci, Elisa Ceccherini, Filippo M Santorelli.
      CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.
    Keywords:  Autophagy; Drug screening; Neuronal ceroid lipofuscinosis 8; Zebrafish
    DOI:  https://doi.org/10.1016/j.nbd.2024.106536
  47. Aging (Albany NY). 2024 May 23. 16
    Sensitivity of substrate translocation in chaperone-mediated autophagy to Alzheimer's disease progression.
    Lei Yu, Xinping Pang, Lin Yang, Kunpei Jin, Wenbo Guo, Yanyu Wei, Chaoyang Pang.
      Alzheimer's disease (AD) is a progressive brain disorder marked by abnormal protein accumulation and resulting proteotoxicity. This study examines Chaperone-Mediated Autophagy (CMA), particularly substrate translocation into lysosomes, in AD. The study observes: (1) Increased substrate translocation activity into lysosomes, vital for CMA, aligns with AD progression, highlighted by gene upregulation and more efficient substrate delivery. (2) This CMA phase strongly correlates with AD's clinical symptoms; more proteotoxicity links to worse dementia, underscoring the need for active degradation. (3) Proteins like GFAP and LAMP2A, when upregulated, almost certainly indicate AD risk, marking this process as a significant AD biomarker. Based on these observations, this study proposes the following hypothesis: As AD progresses, the aggregation of pathogenic proteins increases, the process of substrate entry into lysosomes via CMA becomes active. The genes associated with this process exhibit heightened sensitivity to AD. This conclusion stems from an analysis of over 10,000 genes and 363 patients using two AI methodologies. These methodologies were instrumental in identifying genes highly sensitive to AD and in mapping the molecular networks that respond to the disease, thereby highlighting the significance of this critical phase of CMA.
    Keywords:  Alzheimer’s disease; GFAP; chaperone-mediated autophagy; lysosome
    DOI:  https://doi.org/10.18632/aging.205856
  48. J Biol Chem. 2024 May 20. pii: S0021-9258(24)01899-4. [Epub ahead of print] 107398
    LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome positive cancer cells.
    Nada Amer, Dina Hesham, Nouran Al-Shehaby, Hisham A Elshoky, May Amer, Sameh Magdeldin, Manar Mansour, Khaled Abou-Aisha, Shahenda El-Naggar.
      The unfolded protein response pathways (UPR), autophagy, and compartmentalization of misfolded proteins into inclusion bodies are critical components of the protein quality control network. Among inclusion bodies, aggresomes are particularly intriguing due to their association with cellular survival, drug resistance, and cancer-aggressive behavior. Aggresomes are molecular condensates formed when collapsed vimentin cages encircle misfolded proteins before final removal by autophagy. Yet significant gaps persist in the mechanisms governing aggresome formation and elimination in cancer cells. Understanding these mechanisms is crucial, especially considering the involvement of LC3A, a member of the MAP1LC3 family, which plays a unique role in autophagy regulation and has been reported to be epigenetically silenced in many cancers. Herein, we utilized tetracycline-inducible expression of LC3A to investigate its role in choroid plexus carcinoma cells, which inherently exhibit the presence of aggresomes. Live cell imaging was employed to demonstrate the effect of LC3A expression on aggresome-positive cells, while SILAC-based proteomics identified LC3A-induced protein and pathway alterations. Our findings demonstrate that extended expression of LC3A is associated with cellular senescence. However, the obstruction of lysosomal degradation in this context has a deleterious effect on cellular viability. In response to LC3A-induced autophagy, we observed significant alterations in mitochondrial morphology, reflected by mitochondrial dysfunction and increased ROS production. Furthermore, LC3A expression elicited the activation of the PERK-eIF2α-ATF4 axis of the UPR, underscoring a significant change in protein quality control network. In conclusion, our results elucidate that LC3A-mediated autophagy alters the protein quality control network, exposing a vulnerability in aggresome-positive cancer cells.
    Keywords:  Aggresomes; Autophagy; Endoplasmic reticulum; Inclusion bodies; MAP1LC3A; Protein quality control; Proteostasis; Senescence
    DOI:  https://doi.org/10.1016/j.jbc.2024.107398
  49. Nat Commun. 2024 May 23. 15(1): 4383
    Autophagy-deficient macrophages exacerbate cisplatin-induced mitochondrial dysfunction and kidney injury via miR-195a-5p-SIRT3 axis.
    Yujia Yuan, Longhui Yuan, Jingchao Yang, Fei Liu, Shuyun Liu, Lan Li, Guangneng Liao, Xi Tang, Jingqiu Cheng, Jingping Liu, Younan Chen, Yanrong Lu.
      Macrophages (Mφ) autophagy is a pivotal contributor to inflammation-related diseases. However, the mechanistic details of its direct role in acute kidney injury (AKI) were unclear. Here, we show that Mφ promote AKI progression via crosstalk with tubular epithelial cells (TECs), and autophagy of Mφ was activated and then inhibited in cisplatin-induced AKI mice. Mφ-specific depletion of ATG7 (Atg7Δmye) aggravated kidney injury in AKI mice, which was associated with tubulointerstitial inflammation. Moreover, Mφ-derived exosomes from Atg7Δmye mice impaired TEC mitochondria in vitro, which may be attributable to miR-195a-5p enrichment in exosomes and its interaction with SIRT3 in TECs. Consistently, either miR-195a-5p inhibition or SIRT3 overexpression improved mitochondrial bioenergetics and renal function in vivo. Finally, adoptive transfer of Mφ from AKI mice to Mφ-depleted mice promotes the kidney injury response to cisplatin, which is alleviated when Mφ autophagy is activated with trehalose. We conclude that exosomal miR-195a-5p mediate the communication between autophagy-deficient Mφ and TECs, leading to impaired mitochondrial biogenetic in TECs and subsequent exacerbation of kidney injury in AKI mice via miR-195a-5p-SIRT3 axis.
    DOI:  https://doi.org/10.1038/s41467-024-47842-z
  50. Ecotoxicol Environ Saf. 2024 May 21. pii: S0147-6513(24)00538-4. [Epub ahead of print]279 116462
    Tris(2-ethylhexyl) phosphate induces cytotoxicity in TM3 Leydig cells by modulating autophagy and endoplasmic reticulum stress.
    Wenqiao Zhang, Yali Song, Letai Yi, Jinhuan Ou, Junhui Chen, Wei Zhang, Qinglian Wen, Chuanbin Yang, Jigang Wang.
      Tris (2-ethylhexyl) phosphate (TEHP) is a frequently used organophosphorus flame retardant with significant ecotoxicity and widespread human exposure. Recent research indicates that TEHP has reproductive toxicity. However, the precise cell mechanism is not enough understood. Here, by using testicular mesenchymal stromal TM3 cells as a model, we reveal that TEHP induces apoptosis. Then RNA sequencing analysis, immunofluorescence, and western blotting results show that THEP inhibits autophagy flux and enhances endoplasmic reticulum (ER) stress. Moreover, the activation of the ER stress is critical for TEHP-induced cell injury. Interestingly, TEHP-induced ER stress is contributed to autophagic flux inhibition. Furthermore, pharmacological inhibition of autophagy aggravates, and activation of autophagy attenuates TEHP-induced apoptosis. In summary, these findings indicate that TEHP triggers apoptosis in mouse TM3 cells through ER stress activation and autophagy flux inhibition, offering a new perspective on the mechanisms underlying TEHP-induced interstitial cytotoxicity in the mouse testis.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Reproductive toxicity; Tris (2-ethylhexyl) phosphate
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116462
  51. Int J Mol Sci. 2024 May 16. pii: 5425. [Epub ahead of print]25(10):
    Lon1 Inactivation Downregulates Autophagic Flux and Brassinosteroid Biogenesis, Modulating Mitochondrial Proportion and Seed Development in Arabidopsis.
    Ce Song, Yuqi Hou, Tiantian Li, Yinyin Liu, Xian-Ao Wang, Wumei Qu, Lei Li.
      Mitochondrial protein homeostasis is crucially regulated by protein degradation processes involving both mitochondrial proteases and cytosolic autophagy. However, it remains unclear how plant cells regulate autophagy in the scenario of lacking a major mitochondrial Lon1 protease. In this study, we observed a notable downregulation of core autophagy proteins in Arabidopsis Lon1 knockout mutant lon1-1 and lon1-2, supporting the alterations in the relative proportions of mitochondrial and vacuolar proteins over total proteins in the plant cells. To delve deeper into understanding the roles of the mitochondrial protease Lon1 and autophagy in maintaining mitochondrial protein homeostasis and plant development, we generated the lon1-2atg5-1 double mutant by incorporating the loss-of-function mutation of the autophagy core protein ATG5, known as atg5-1. The double mutant exhibited a blend of phenotypes, characterized by short plants and early senescence, mirroring those observed in the individual single mutants. Accordingly, distinct transcriptome alterations were evident in each of the single mutants, while the double mutant displayed a unique amalgamation of transcriptional responses. Heightened severity, particularly evident in reduced seed numbers and abnormal embryo development, was observed in the double mutant. Notably, aberrations in protein storage vacuoles (PSVs) and oil bodies were evident in the single and double mutants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of genes concurrently downregulated in lon1-2, atg5-1, and lon1-2atg5-1 unveiled a significant suppression of genes associated with brassinosteroid (BR) biosynthesis and homeostasis. This downregulation likely contributes to the observed abnormalities in seed and embryo development in the mutants.
    Keywords:  Arabidopsis; Lon1; autophagy; brassinosteroid; mitochondrion
    DOI:  https://doi.org/10.3390/ijms25105425
  52. World J Urol. 2024 May 18. 42(1): 333
    Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.
    Song Jin, Zhanliang Liu, Peng Xiang, Meng Fu, Gang Zhang, Jianxing Li, Yinong Niu.
       PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients.
    METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation.
    RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway.
    CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.
    Keywords:  Autophagy; Benign prostatic hyperplasia; Fibroblast activation; Phosphodiesterase type 5 inhibitor
    DOI:  https://doi.org/10.1007/s00345-024-04956-9
  53. Metabolites. 2024 Apr 25. pii: 248. [Epub ahead of print]14(5):
    The Metabolic and Lipidomic Fingerprint of Torin1 Exposure in Mouse Embryonic Fibroblasts Using Untargeted Metabolomics.
    Rani Robeyns, Angela Sisto, Elias Iturrospe, Katyeny Manuela da Silva, Maria van de Lavoir, Vincent Timmerman, Adrian Covaci, Sigrid Stroobants, Alexander L N van Nuijs.
      Torin1, a selective kinase inhibitor targeting the mammalian target of rapamycin (mTOR), remains widely used in autophagy research due to its potent autophagy-inducing abilities, regardless of its unspecific properties. Recognizing the impact of mTOR inhibition on metabolism, our objective was to develop a reliable and thorough untargeted metabolomics workflow to study torin1-induced metabolic changes in mouse embryonic fibroblast (MEF) cells. Crucially, our quality assurance and quality control (QA/QC) protocols were designed to increase confidence in the reported findings by reducing the likelihood of false positives, including a validation experiment replicating all experimental steps from sample preparation to data analysis. This study investigated the metabolic fingerprint of torin1 exposure by using liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics platforms. Our workflow identified 67 altered metabolites after torin1 exposure, combining univariate and multivariate statistics and the implementation of a validation experiment. In particular, intracellular ceramides, diglycerides, phosphatidylcholines, phosphatidylethanolamines, glutathione, and 5'-methylthioadenosine were downregulated. Lyso-phosphatidylcholines, lyso-phosphatidylethanolamines, glycerophosphocholine, triglycerides, inosine, and hypoxanthine were upregulated. Further biochemical pathway analyses provided deeper insights into the reported changes. Ultimately, our study provides a valuable workflow that can be implemented for future investigations into the effects of other compounds, including more specific autophagy modulators.
    Keywords:  autophagy; high-resolution mass spectrometry; lipids; mTOR; metabolism
    DOI:  https://doi.org/10.3390/metabo14050248
  54. Can J Physiol Pharmacol. 2024 May 22.
    Chloramphenicol alleviates 5-fluorouracil-induced cellular senescence through activation of autophagy.
    Shirui Bai, Qi Zhao, Hui-Jie Jia, Fei He, Xiao-Bo Wang.
      5-Fluorouracil (5-FU) is a first-line treatment for colorectal cancer, but side effects such as severe diarrhea are common in clinical use and have been linked to its induction of normal cell senescence. Chloramphenicol (CAP) is an antibiotic commonly used to treat typhoid or anaerobic infections, but its senescence-related aspects have not been thoroughly investigated. Here, we used 5-FU to induce senescence in human umbilical vein endothelial cells (HUVECs) and investigated the relationship between CAP and cellular senescence at the cellular level. In a model of cellular senescence induced by 5-FU treatment, we discovered that CAP treatment reversed the rise in the percentage of senescence-associated galactosidase (SA-β-gal)-positive cells and decreased the expression of senescence-associated proteins (p16), senescence-associated genes (p21), and senescence-associated secretory phenotypes (SASPs: IL-6, TNF-α). In addition, CAP subsequently restored the autophagic process inhibited by 5-FU and upregulated the levels of autophagy-related proteins. Mechanistically, we found that CAP restored autophagic flux by inhibiting the mTOR pathway, which in turn alleviated FU-induced cellular senescence. Our findings suggest that CAP may help prevent cellular senescence and restore autophagy, opening up new possibilities and approaches for the clinical management of colorectal cancer.
    DOI:  https://doi.org/10.1139/cjpp-2023-0432
  55. J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107403
  56. Epilepsia. 2024 May 18.
    A role of dentate gyrus mechanistic target of rapamycin activation in epileptogenesis in a mouse model of posttraumatic epilepsy.
    Dongjun Guo, Lirong Han, Christin M Godale, Nicholas R Rensing, Steve C Danzer, Michael Wong.
       OBJECTIVE: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI.
    METHODS: An adeno-associated virus (AAV)-Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory-associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV-Cre or AAV-vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video-electroencephalographic monitoring.
    RESULTS: AAV-Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV-Cre-injected mice had reduced neuronal death in dentate gyrus detected by Fluoro-Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV-Cre-injected mice exhibited a decrease in incidence of PTE.
    SIGNIFICANCE: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE.
    Keywords:  Raptor; hippocampus; mice; rapamycin; seizure
    DOI:  https://doi.org/10.1111/epi.18011
  57. Nat Cell Biol. 2024 May 23.
    TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
    Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.
      When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01419-6
  58. Inflammation. 2024 May 19.
    Periodontopathogen-Related Cell Autophagy-A Double-Edged Sword.
    Li Ma, Zhengguo Cao.
      The periodontium is a highly organized ecosystem, and the imbalance between oral microorganisms and host defense leads to periodontal diseases. The periodontal pathogens, mainly Gram-negative anaerobic bacteria, colonize the periodontal niches or enter the blood circulation, resulting in periodontal tissue destruction and distal organ damage. This phenomenon links periodontitis with various systemic conditions, including cardiovascular diseases, malignant tumors, steatohepatitis, and Alzheimer's disease. Autophagy is an evolutionarily conserved cellular self-degradation process essential for eliminating internalized pathogens. Nowadays, increasing studies have been carried out in cells derived from periodontal tissues, immune system, and distant organs to investigate the relationship between periodontal pathogen infection and autophagy-related activities. On one hand, as a vital part of innate and adaptive immunity, autophagy actively participates in host resistance to periodontal bacterial infection. On the other, certain periodontal pathogens exploit autophagic vesicles or pathways to evade immune surveillance, therefore achieving survival within host cells. This review provides an overview of the autophagy process and focuses on periodontopathogen-related autophagy and their involvements in cells of different tissue origins, so as to comprehensively understand the role of autophagy in the occurrence and development of periodontal diseases and various periodontitis-associated systemic illnesses.
    Keywords:   Porphyromonas gingivalis.; autophagic cell death; autophagy; periodontal pathogen; periodontitis; systemic diseases
    DOI:  https://doi.org/10.1007/s10753-024-02049-8
  59. Int Immunopharmacol. 2024 May 20. pii: S1567-5769(24)00763-X. [Epub ahead of print]135 112244
    Exploring the role of autophagy in psoriasis pathogenesis: Insights into sustained inflammation and dysfunctional keratinocyte differentiation.
    Xinxin Wu, Jiankun Song, Ying Zhang, Le Kuai, Changya Liu, Xin Ma, Bin Li, Zhan Zhang, Ying Luo.
      Psoriasis is a common and prevalent chronic papulosquamous cutaneous disorder characterized by sustained inflammation, uncontrolled keratinocyte proliferation, dysfunctional differentiation, and angiogenesis. Autophagy, an intracellular catabolic process, can be induced in response to nutrient stress. It entails the degradation of cellular constituents through the lysosomal machinery, and its association with psoriasis has been well-documented. Nevertheless, there remains a notable dearth of research concerning the involvement of autophagy in the pathogenesis of psoriasis within human skin. This review provides a comprehensive overview of autophagy in psoriasis pathogenesis, focusing on its involvement in two key pathological manifestations: sustained inflammation and uncontrolled keratinocyte proliferation and differentiation. Additionally, it discusses potential avenues for disease management.
    Keywords:  Angiogenesis; Autophagy; Differentiation; Inflammation; Proliferation; Psoriasis
    DOI:  https://doi.org/10.1016/j.intimp.2024.112244
  60. Research (Wash D C). 2024 ;7 0380
    USP18 Antagonizes Pyroptosis by Facilitating Selective Autophagic Degradation of Gasdermin D.
    Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Yaoxing Wu, Jun Cui.
      As a key executioner of pyroptosis, Gasdermin D (GSDMD) plays a crucial role in host defense and emerges as an essential therapeutic target in the treatment of inflammatory diseases. So far, the understanding of the mechanisms that regulate the protein level of GSDMD to prevent detrimental effects and maintain homeostasis is currently limited. Here, we unveil that ubiquitin-specific peptidase 18 (USP18) works as a negative regulator of pyroptosis by targeting GSDMD for degradation and preventing excessive innate immune responses. Mechanically, USP18 recruits E3 ubiquitin ligase mind bomb homolog 2 (MIB2) to catalyze ubiquitination on GSDMD at lysine (K) 168, which acts as a recognition signal for the selective autophagic degradation of GSDMD. We further confirm the alleviating effect of USP18 on LPS-triggered inflammation in vivo. Collectively, our study demonstrates the role of USP18 in regulating GSDMD-mediated pyroptosis and reveals a previously unknown mechanism by which GSDMD protein level is rigorously controlled by selective autophagy.
    DOI:  https://doi.org/10.34133/research.0380
  61. Redox Biol. 2024 May 16. pii: S2213-2317(24)00174-5. [Epub ahead of print]73 103196
    Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.
    Jingyan Shen, Pengfei Xie, Junhan Wang, Fan Yang, Shengjie Li, Haitao Jiang, Xuefeng Wu, Feng Zhou, Jianmei Li.
      Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.
    Keywords:  Cognitive defects; Mitochondrial disorders; Mitophagy; NOD-Like receptor family pyrin domain-containing 6; NSPC ferroptosis
    DOI:  https://doi.org/10.1016/j.redox.2024.103196
  62. J Mammary Gland Biol Neoplasia. 2024 May 18. 29(1): 11
    Methods for investigating STAT3 regulation of lysosomal function in mammary epithelial cells.
    Bethan Lloyd-Lewis, Michael E D'Angelo, Neve B Prowting, Bethan E Wiseman, Timothy J Sargeant, Christine J Watson.
      The transcription factor STAT3 is activated by multiple cytokines and other extrinsic factors. It plays a key role in immune and inflammatory responses and, when dysregulated, in tumourigenesis. STAT3 is also an indispensable mediator of the cell death process that occurs during post-lactational regression of the mammary gland, one of the most dramatic examples of physiological cell death in adult mammals. During this involution of the gland, STAT3 powerfully enhances the lysosomal system to efficiently remove superfluous milk-producing mammary epithelial cells via a lysosomal-mediated programmed cell death pathway. The lysosome is a membrane-enclosed  cytoplasmic organelle that digests and recycles cellular waste, with an important role as a signalling centre that monitors cellular metabolism. Here, we describe key strategies for investigating the role of STAT3 in regulating lysosomal function using a mammary epithelial cell culture model system. These include protocols for lysosome enrichment and enzyme activity assays, in addition to microscopic analyses of the vesicular compartment in cell lines. Collectively, these approaches provide the tools to investigate multiple aspects of lysosome biogenesis and function, and to define both direct and indirect roles for STAT3.
    Keywords:  Cell death; Lysoptosis; Lysosome; Lysosome-mediated programmed cell death; Mammary gland; STAT3 signalling
    DOI:  https://doi.org/10.1007/s10911-024-09563-3
  63. Nat Rev Cardiol. 2024 May 21.
    Artificially transplanted mitochondria in endothelial cells promote mitophagy.
    Karina Huynh.
      
    DOI:  https://doi.org/10.1038/s41569-024-01041-x
  64. Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2318412121
    Ca2+-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress.
    Wei Chen, Madeline M Motsinger, Jiaqian Li, Kevin P Bohannon, Phyllis I Hanson.
      Lysosomes are central players in cellular catabolism, signaling, and metabolic regulation. Cellular and environmental stresses that damage lysosomal membranes can compromise their function and release toxic content into the cytoplasm. Here, we examine how cells respond to osmotic stress within lysosomes. Using sensitive assays of lysosomal leakage and rupture, we examine acute effects of the osmotic disruptant glycyl-L-phenylalanine 2-naphthylamide (GPN). Our findings reveal that low concentrations of GPN rupture a small fraction of lysosomes, but surprisingly trigger Ca2+ release from nearly all. Chelating cytoplasmic Ca2+ makes lysosomes more sensitive to GPN-induced rupture, suggesting a role for Ca2+ in lysosomal membrane resilience. GPN-elicited Ca2+ release causes the Ca2+-sensor Apoptosis Linked Gene-2 (ALG-2), along with Endosomal Sorting Complex Required for Transport (ESCRT) proteins it interacts with, to redistribute onto lysosomes. Functionally, ALG-2, but not its ESCRT binding-disabled ΔGF122 splice variant, increases lysosomal resilience to osmotic stress. Importantly, elevating juxta-lysosomal Ca2+ without membrane damage by activating TRPML1 also recruits ALG-2 and ESCRTs, protecting lysosomes from subsequent osmotic rupture. These findings reveal that Ca2+, through ALG-2, helps bring ESCRTs to lysosomes to enhance their resilience and maintain organelle integrity in the face of osmotic stress.
    Keywords:  ALG-2; ESCRTs; lysosome; membrane resilience; osmotic stress
    DOI:  https://doi.org/10.1073/pnas.2318412121
  65. Virol J. 2024 May 22. 21(1): 114
    EV71 5'UTR interacts with 3D protein affecting replication through the AKT-mTOR pathway.
    Xiaoying Xu, Shao Ma, Ziwei Liu, Haowen Yuan, Yao Wang, Mengting Chen, Mengyu Du, Haopeng Kan, Zequn Wang, Xiaowen Chong, Hongling Wen.
       BACKGROUND: EV71 is one of the important pathogens of Hand-foot-and-mouth disease (HFMD), which causes serious neurological symptoms. Several studies have speculated that there will be interaction between 5'UTR and 3D protein. However, whether 5'UTR interacts with the 3D protein in regulating virus replication has not been clarified.
    METHODS: Four 5'UTR mutation sites (nt88C/T, nt90-102-3C, nt157G/A and nt574T/A) and two 3D protein mutation sites (S37N and R142K) were mutated or co-mutated using virulent strains as templates. The replication of these mutant viruses and their effect on autophagy were determined.
    RESULTS: 5'UTR single-point mutant strains, except for EGFP-EV71(nt90-102-3C), triggered replication attenuation. The replication ability of them was weaker than that of the parent strain the virulent strain SDLY107 which is the fatal strain that can cause severe neurological complications. While the replication level of the co-mutant strains showed different characteristics. 5 co-mutant strains with interaction were screened: EGFP-EV71(S37N-nt88C/T), EGFP-EV71(S37N-nt574T/A), EGFP-EV71(R142K-nt574T/A), EGFP-EV71(R142K-nt88C/T), and EGFP-EV71(R142K-nt157G/A). The results showed that the high replicative strains significantly promoted the accumulation of autophagosomes in host cells and hindered the degradation of autolysosomes. The low replicative strains had a low ability to regulate the autophagy of host cells. In addition, the high replicative strains also significantly inhibited the phosphorylation of AKT and mTOR.
    CONCLUSIONS: EV71 5'UTR interacted with the 3D protein during virus replication. The co-mutation of S37N and nt88C/T, S37N and nt574T/ A, R142K and nt574T/A induced incomplete autophagy of host cells and promoted virus replication by inhibiting the autophagy pathway AKT-mTOR. The co-mutation of R142K and nt88C/T, and R142K and nt157G/A significantly reduced the inhibitory effect of EV71 on the AKT-mTOR pathway and reduced the replication ability of the virus.
    Keywords:  3D protein; 5′UTR; AKT-mTOR pathway; Autophagy; Co-mutation; EV71
    DOI:  https://doi.org/10.1186/s12985-024-02385-z
  66. Int J Mol Sci. 2024 May 07. pii: 5101. [Epub ahead of print]25(10):
    p20BAP31 Induces Autophagy in Colorectal Cancer Cells by Promoting PERK-Mediated ER Stress.
    Xiaohan Jiang, Guoxun Li, Benzhi Zhu, Jiaying Yang, Shuyu Cui, Rui Jiang, Bing Wang.
      B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum (ER) membrane protein involved in apoptosis and autophagy by communication with ER and mitochondria. BAP31 is cleaved by caspase-8 and generates a proapoptotic fragment, p20BAP31, which has shown to induce ER stress and apoptosis through multiple pathways. In this study, we found that p20BAP31 significantly increased the agglomeration of LC3 puncta, suggesting the occurrence of autophagy. Therefore, it is meaningful to explore the mechanism of p20BAP31-induced autophagy, and further analyze the relationships among p20BAP31-induced autophagy, ER stress and apoptosis. The data showed that p20BAP31 induced autophagy by inhibition of the PI3K/AKT/mTOR signaling in colorectal cells. ER stress inhibitor 4-PBA and PERK siRNA alleviated p20BAP31-induced autophagy; in turn, autophagy inhibitors 3-MA and CQ did not affect p20BAP31-induced ER stress, suggesting that p20BAP31-induced ER stress is the upstream of autophagy. We also discovered that ROS inhibitor NAC inhibited p20BAP31-induced autophagy. Furthermore, inhibition of autophagy by CQ suppressed p20BAP31-induced apoptosis and ameliorated cell proliferation. Importantly, p20BAP31 markedly reduced the tumor size in vivo, and significantly enhanced the autophagy levels in the tumor tissues. Collectively, p20BAP31 initiates autophagy by inhibiting the PI3K/AKT/mTOR signaling and activating the PERK-mediated ROS accumulation, further promotes p20BAP31-induced apoptosis and ultimately results in cell death. This study comprehensively reveals the potential mechanism of p20BAP31-induced cell death, which may provide new strategies for antitumor therapy.
    Keywords:  ER stress; PI3K/AKT/mTOR; apoptosis; autophagy; colorectal cancer; p20BAP31
    DOI:  https://doi.org/10.3390/ijms25105101
  67. mBio. 2024 May 20. e0086224
    mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.
    Christopher J Genito, Benjamin P Darwitz, Callista P Reber, Nathaniel J Moorman, Christina L Graves, Andrew J Monteith, Lance R Thurlow.
      Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.
    Keywords:  Staphylococcus aureus; immune dysfunction; mTOR
    DOI:  https://doi.org/10.1128/mbio.00862-24
  68. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00014-5. [Epub ahead of print]386 81-131
    An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.
    Shovan Dutta, Anirban Ganguly, Sounak Ghosh Roy.
      Autophagy and Unfolded Protein Response (UPR) can be regarded as the safe keepers of cells exposed to intense stress. Autophagy maintains cellular homeostasis, ensuring the removal of foreign particles and misfolded macromolecules from the cytoplasm and facilitating the return of the building blocks into the system. On the other hand, UPR serves as a shock response to prolonged stress, especially Endoplasmic Reticulum Stress (ERS), which also includes the accumulation of misfolded proteins in the ER. Since one of the many effects of viral infection on the host cell machinery is the hijacking of the host translational system, which leaves in its wake a plethora of misfolded proteins in the ER, it is perhaps not surprising that UPR and autophagy are common occurrences in infected cells, tissues, and patient samples. In this book chapter, we try to emphasize how UPR, and autophagy are significant in infections caused by six major oncolytic viruses-Epstein-Barr (EBV), Human Papilloma Virus (HPV), Human Immunodeficiency Virus (HIV), Human Herpesvirus-8 (HHV-8), Human T-cell Lymphotropic Virus (HTLV-1), and Hepatitis B Virus (HBV). Here, we document how whole-virus infection or overexpression of individual viral proteins in vitro and in vivo models can regulate the different branches of UPR and the various stages of macro autophagy. As is true with other viral infections, the relationship is complicated because the same virus (or the viral protein) exerts different effects on UPR and Autophagy. The nature of this response is determined by the cell types, or in some cases, the presence of diverse extracellular stimuli. The vice versa is equally valid, i.e., UPR and autophagy exhibit both anti-tumor and pro-tumor properties based on the cell type and other factors like concentrations of different metabolites. Thus, we have tried to coherently summarize the existing knowledge, the crux of which can hopefully be harnessed to design vaccines and therapies targeted at viral carcinogenesis.
    Keywords:  ATF6; Autophagy; CHOP; EBV; ERS; HHV-8; HIV; HPV; HTLV-1; IRE1-α; PERK; UPR
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.01.004
  69. J Clin Med. 2024 May 20. pii: 3005. [Epub ahead of print]13(10):
    Autophagy in Osteoarthritis: A Double-Edged Sword in Cartilage Aging and Mechanical Stress Response: A Systematic Review.
    Dong-Yeong Lee, Md Entaz Bahar, Chang-Won Kim, Min-Seok Seo, Myung-Geun Song, Sang-Youn Song, Soung-Yon Kim, Deok-Ryong Kim, Dong-Hee Kim.
      Background: Although osteoarthritis (OA) development is epidemiologically multifactorial, a primary underlying mechanism is still under debate. Understanding the pathophysiology of OA remains challenging. Recently, experts have focused on autophagy as a contributor to OA development. Method: To better understand the pathogenesis of OA, we survey the literature on the role of autophagy and the molecular mechanisms of OA development. To identify relevant studies, we used controlled vocabulary and free text keywords to search the MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and SCOPUS database. Thirty-one studies were included for data extraction and systematic review. Among these studies, twenty-five studies investigated the effects of autophagy in aging and OA chondrocytes, six studies examined the effects of autophagy in normal human chondrocytes, and only one study investigated the effects of mechanical stress-induced autophagy on the development of OA in normal chondrocytes. Results: The studies suggest that autophagy activation prevents OA by exerting cell-protective effects in normal human chondrocytes. However, in aging and osteoarthritis (OA) chondrocytes, the role of autophagy is intricate, as certain studies indicate that stimulating autophagy in these cells can have a cytotoxic effect, while others propose that it may have a protective (cytoprotective) effect against damage or degeneration. Conclusions: Mechanical stress-induced autophagy is also thought to be involved in the development of OA, but further research is required to identify the precise mechanism. Thus, autophagy contributions should be interpreted with caution in aging and the types of OA cartilage.
    Keywords:  arthritis; autophagy; cartilage; chondrocyte; osteoarthritis
    DOI:  https://doi.org/10.3390/jcm13103005
  70. J Invest Dermatol. 2024 May 17. pii: S0022-202X(24)00374-9. [Epub ahead of print]
    Biomechanical activation of keloid fibroblasts promotes lysosomal remodelling and exocytosis.
    Rosie Ross, Yiyang Guo, Rebecca N Walker, Daniele Bergamaschi, Tanya J Shaw, John T Connelly.
      Keloids are a severe form of scarring for which the underlying mechanisms are poorly understood, and treatment options are limited or inconsistent. While biomechanical forces are potential drivers of keloid scarring, the direct cellular responses to mechanical cues have yet to be defined. The aim of this study was to examine the distinct responses of normal dermal fibroblasts (NDFs) and keloid-derived fibroblasts (KDFs) to changes in extracellular matrix (ECM) stiffness. When cultured on hydrogels mimicking the elasticity of normal or scarred skin, KDFs displayed greater stiffness-dependent increases in cell spreading, F-actin stress fibre formation, and focal adhesion assembly. Elevated acto-myosin contractility in KDFs disrupted the normal mechanical regulation of ECM deposition and conferred resistance myosin inhibitors. Transcriptional profiling identified mechanically-regulated pathways in NDFs and KDFs, including the actin cytoskeleton, Hippo signalling, and autophagy. Further analysis of the autophagy pathway revealed that autophagic flux was intact in both fibroblast populations and depended on acto-myosin contractility. However, KDFs displayed marked changes in lysosome organisation and an increase in lysosomal exocytosis, which was mediated by acto-myosin contractility. Together, these findings demonstrate that KDFs possess an intrinsic increase in cytoskeletal tension, which heightens the response to ECM mechanics and promotes lysosomal exocytosis.
    Keywords:  autophagy; biomechanics; cytoskeleton; lysosome; scar
    DOI:  https://doi.org/10.1016/j.jid.2024.04.015
  71. Cell Mol Life Sci. 2024 May 23. 81(1): 232
    Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson's disease.
    Liuyan Ding, Lin Lu, Shaohui Zheng, Zhiling Zhang, Xingting Huang, Runfang Ma, Mengran Zhang, Zongtang Xu, Minshan Chen, Zhimei Guo, Si Zhu, Junwei Gong, Hengxu Mao, Wenlong Zhang, Pingyi Xu.
      Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.
    Keywords:  Autophagy; Parkinson’s disease; S100A8/A9; USP14; α-synuclein
    DOI:  https://doi.org/10.1007/s00018-024-05246-8
  72. Nat Struct Mol Biol. 2024 May 20.
    Structure and mechanism of lysosome transmembrane acetylation by HGSNAT.
    Ruisheng Xu, Yingjie Ning, Fandong Ren, Chenxia Gu, Zhengjiang Zhu, Xuefang Pan, Alexey V Pshezhetsky, Jingpeng Ge, Jie Yu.
      Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), whose dysfunction leads to lysosomal storage diseases. The mechanism by which HGSNAT, the sole non-hydrolase enzyme in HS degradation, brings cytosolic acetyl-coenzyme A (Ac-CoA) and lysosomal HS together for N-acyltransferase reactions remains unclear. Here, we present cryogenic-electron microscopy structures of HGSNAT alone, complexed with Ac-CoA and with acetylated products. These structures explain that Ac-CoA binding from the cytosolic side causes dimeric HGSNAT to form a transmembrane tunnel. Within this tunnel, catalytic histidine and asparagine approach the lumen and instigate the transfer of the acetyl group from Ac-CoA to the glucosamine group of HS. Our study unveils a transmembrane acetylation mechanism that may help advance therapeutic strategies targeting lysosomal storage diseases.
    DOI:  https://doi.org/10.1038/s41594-024-01315-5
  73. J Neurochem. 2024 May 17.
    Sestrin2 remedies neuroinflammatory response by inhibiting A1 astrocyte conversion via autophagy.
    Zhenguo Pan, Xiaoyu Yu, Weiwei Wang, Kai Shen, Jianwei Chen, Yunfeng Zhang, Rongrong Huang.
      Most central nervous diseases are accompanied by astrocyte activation. Autophagy, an important pathway for cells to protect themselves and maintain homeostasis, is widely involved in regulation of astrocyte activation. Reactive astrocytes may play a protective or harmful role in different diseases due to different phenotypes of astrocytes. It is an urgent task to clarify the formation mechanisms of inflammatory astrocyte phenotype, A1 astrocytes. Sestrin2 is a highly conserved protein that can be induced under a variety of stress conditions as a potential protective role in oxidative damage process. However, whether Sestrin2 can affect autophagy and involve in A1 astrocyte conversion is still uncovered. In this study, we reported that Sestrin2 and autophagy were significantly induced in mouse hippocampus after multiple intraperitoneal injections of lipopolysaccharide, with the elevation of A1 astrocyte conversion and inflammatory mediators. Knockdown Sestrin2 in C8-D1A astrocytes promoted the levels of A1 astrocyte marker C3 mRNA and inflammatory factors, which was rescued by autophagy inducer rapamycin. Overexpression of Sestrin2 in C8-D1A astrocytes attenuated A1 astrocyte conversion and reduced inflammatory factor levels via abundant autophagy. Moreover, Sestrin2 overexpression improved mitochondrial structure and morphology. These results suggest that Sestrin2 can suppress neuroinflammation by inhibiting A1 astrocyte conversion via autophagy, which is a potential drug target for treating neuroinflammation.
    Keywords:  Sestrin2; astrocyte phenotype; autophagy; inflammation; mitochondria
    DOI:  https://doi.org/10.1111/jnc.16126
  74. FASEB J. 2024 May 31. 38(10): e23655
    Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy.
    Ning Jin, Mengyao Zhang, Li Zhou, Shanshan Jin, Haiqin Cheng, Xuewei Li, Yaqian Shi, Tong Xiang, Zongxiao Zhang, Zhizhen Liu, Hong Zhao, Jun Xie.
      The disruption of mitochondria homeostasis can impair the contractile function of cardiomyocytes, leading to cardiac dysfunction and an increased risk of heart failure. This study introduces a pioneering therapeutic strategy employing mitochondria derived from human umbilical cord mesenchymal stem cells (hu-MSC) (MSC-Mito) for heart failure treatment. Initially, we isolated MSC-Mito, confirming their functionality. Subsequently, we monitored the process of single mitochondria transplantation into recipient cells and observed a time-dependent uptake of mitochondria in vivo. Evidence of human-specific mitochondrial DNA (mtDNA) in murine cardiomyocytes was observed after MSC-Mito transplantation. Employing a doxorubicin (DOX)-induced heart failure model, we demonstrated that MSC-Mito transplantation could safeguard cardiac function and avert cardiomyocyte apoptosis, indicating metabolic compatibility between hu-MSC-derived mitochondria and recipient mitochondria. Finally, through RNA sequencing and validation experiments, we discovered that MSC-Mito transplantation potentially exerted cardioprotection by reinstating ATP production and curtailing AMPKα-mTOR-mediated excessive autophagy.
    Keywords:  AMPKα‐mTOR; ATP; autophagy; cardiomyocyte apoptosis; mitochondria transplantation
    DOI:  https://doi.org/10.1096/fj.202400375R
  75. Phytomedicine. 2024 May 06. pii: S0944-7113(24)00380-5. [Epub ahead of print]130 155721
    Urolithin A, induces apoptosis and autophagy crosstalk in Oral Squamous Cell Carcinoma via mTOR /AKT/ERK1/2 pathway.
    Viji Remadevi, Vishnu Sunil Jaikumar, Ravindran Vini, Biju Krishnendhu, Juberiya M Azeez, Sankar Sundaram, S Sreeja.
       BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in the world with an alarming rate of mortality. Despite the advancement in treatment strategies and drug developments, the overall survival rate remains poor. Therefore, it is imperative to develop alternative or complimentary anti cancer drugs with minimum off target effects. Urolithin A, a microbial metabolite of ellagic acid and ellagitannins produced endogenously by human gut micro biome is considered to have anti-cancerous activity. However anti tumorigenic effect of urolithin A in OSCC is yet to be elucidated. In this study, we examined whether urolithin A inhibits cell growth and induces both apoptosis and autophagy dependent cell death in OSCC cell lines.
    PURPOSE: The present study aims to evaluate the potential of urolithin A to inhibit OSCC and its regulatory effect on OSCC proliferation and invasion in vitro and in vivo mouse models.
    METHODS: We evaluated whether urolithin A could induce cell death in OSCC in vitro and in vivo mouse models.
    RESULTS: Flow cytometric and immunoblot analysis on Urolithin A treated OSCC cell lines revealed that urolithin A markedly induced cell death of OSCC via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. This further revealed a possible cross talk between apoptotic and autophagic signaling pathways. In vivo study demonstrated that urolithin A treatment reduced tumor size and showed a decrease in mTOR, ERK1/2 and Akt levels along with a decrease in proliferation marker, Ki67. Taken together, in vitro as well as our in vivo data indicates that urolithin A is a potential anticancer agent and the inhibition of AKT/mTOR/ERK signalling is crucial in Urolithin A induced growth suppression in oral cancer.
    CONCLUSION: Urolithin A exerts its anti tumorigenic activity through the induction of apoptotic and autophagy pathways in OSCC. Our findings suggest that urolithin A markedly induced cell death of oral squamous cell carcinoma via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. Urolithin A remarkably suppressed tumor growth in both in vitro and in vivo mouse models signifying its potential as an anticancer agent in the prevention and treatment of OSCC. Henceforth, our findings provide a new insight into the therapeutic potential of urolithin A in the prevention and treatment of OSCC.
    Keywords:  AKT/MTOR/ERK signaling; Apoptosis; Autophagy; OSCC; Urolithin A
    DOI:  https://doi.org/10.1016/j.phymed.2024.155721
  76. Heliyon. 2024 May 30. 10(10): e30568
    SIRT3 and RORα are two prospective targets against mitophagy during simulated ischemia/reperfusion injury in H9c2 cells.
    Jinjing Wu, Yanli Yang, Duomao Lin, Zhaoqi Wang, Jun Ma.
      Autophagy during myocardial ischemia/reperfusion (MI/R) exacerbates cardiomyocyte injury. Melatonin (Mel) alleviates myocardial damage by regulating mitochondrial function and mitophagy, but the role of mitophagy in melatonin-induced cardioprotection remains unclear. This study aimed to explore the roles of sirtuin3 (SIRT3) and retinoid-related orphan nuclear receptor-α (RORα) in mitophagy during simulated ischemia reperfusion (SIR) in H9c2 cells. Our data showed that mitophagy was excessively activated after SIR injury, which was consistent with reduced cell survival, enhanced oxidative responses and mitochondrial dysfunction in H9c2 myocytes. Melatonin greatly enhanced cell viability, reduced oxidative stress and improved mitochondrial function. The effects of melatonin protection were involved in excessive mitophagy inhibition, as demonstrated by the reduced levels of mitophagy-linked proteins, including Parkin, Beclin1, NIX and BNIP3, and the LC3 II/LC3 I ratio and elevations in p62. Additionally, the decreases in SIRT3 and RORα in H9c2 myocytes after SIR were reversed by melatonin, and the above effects of melatonin were eliminated by small interfering RNA (siRNA)-mediated knockdown of SIRT3 and RORα. In brief, SIRT3 and RORα are two prospective targets in the cardioprotection of melatonin against mitophagy during SIR in H9c2 myocytes.
    Keywords:  Ischemia reperfusion; Melatonin; Mitophagy; Nuclear receptor; SIRT3
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30568
  77. Front Med. 2024 May 21.
    Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis.
    Yue Yuan, Jiaxuan Li, Xun Lu, Min Chen, Huifang Liang, Xiao-Ping Chen, Xin Long, Bixiang Zhang, Song Gong, Xiaowei Huang, Jianping Zhao, Qian Chen.
      Schistosoma infection is one of the major causes of liver fibrosis. Emerging roles of hepatic progenitor cells (HPCs) in the pathogenesis of liver fibrosis have been identified. Nevertheless, the precise mechanism underlying the role of HPCs in liver fibrosis in schistosomiasis remains unclear. This study examined how autophagy in HPCs affects schistosomiasis-induced liver fibrosis by modulating exosomal miRNAs. The activation of HPCs was verified by immunohistochemistry (IHC) and immunofluorescence (IF) staining in fibrotic liver from patients and mice with Schistosoma japonicum infection. By coculturing HPCs with hepatic stellate cells (HSCs) and assessing the autophagy level in HPCs by proteomic analysis and in vitro phenotypic assays, we found that impaired autophagy degradation in these activated HPCs was mediated by lysosomal dysfunction. Blocking autophagy by the autophagy inhibitor chloroquine (CQ) significantly diminished liver fibrosis and granuloma formation in S. japonicum-infected mice. HPC-secreted extracellular vehicles (EVs) were further isolated and studied by miRNA sequencing. miR-1306-3p, miR-493-3p, and miR-34a-5p were identified, and their distribution into EVs was inhibited due to impaired autophagy in HPCs, which contributed to suppressing HSC activation. In conclusion, we showed that the altered autophagy process upon HPC activation may prevent liver fibrosis by modulating exosomal miRNA release and inhibiting HSC activation in schistosomiasis. Targeting the autophagy degradation process may be a therapeutic strategy for liver fibrosis during Schistosoma infection.
    Keywords:  autophagy; extracellular vesicle; fibrosis; hepatic progenitor cell; miRNA; schistosomiasis
    DOI:  https://doi.org/10.1007/s11684-024-1079-1
  78. Adv Sci (Weinh). 2024 May 22. e2306912
    The Spermine Oxidase/Spermine Axis Coordinates ATG5-Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis.
    Dan Luo, Xiaohui Lu, Hongyu Li, Yi Li, Yating Wang, Simin Jiang, Guanglan Li, Yiping Xu, Kefei Wu, Xianrui Dou, Qinghua Liu, Wei Chen, Yi Zhou, Haiping Mao.
      Decreased plasma spermine levels are associated with kidney dysfunction. However, the role of spermine in kidney disease remains largely unknown. Herein, it is demonstrated that spermine oxidase (SMOX), a key enzyme governing polyamine metabolism, is predominantly induced in tubular epithelium of human and mouse fibrotic kidneys, alongside a reduction in renal spermine content in mice. Moreover, renal SMOX expression is positively correlated with kidney fibrosis and function decline in patients with chronic kidney disease. Importantly, supplementation with exogenous spermine or genetically deficient SMOX markedly improves autophagy, reduces senescence, and attenuates fibrosis in mouse kidneys. Further, downregulation of ATG5, a critical component of autophagy, in tubular epithelial cells enhances SMOX expression and reduces spermine in TGF-β1-induced fibrogenesis in vitro and kidney fibrosis in vivo. Mechanically, ATG5 readily interacts with SMOX under physiological conditions and in TGF-β1-induced fibrogenic responses to preserve cellular spermine levels. Collectively, the findings suggest SMOX/spermine axis is a potential novel therapy to antagonize renal fibrosis, possibly by coordinating autophagy and suppressing senescence.
    Keywords:  SMOX; autophagy; cell senescence; renal fibrosis; spermine
    DOI:  https://doi.org/10.1002/advs.202306912
  79. Viruses. 2024 Apr 29. pii: 702. [Epub ahead of print]16(5):
    HACD3 Prevents PB1 from Autophagic Degradation to Facilitate the Replication of Influenza A Virus.
    Qibing Li, Li Jiang, Yihan Wang, Xuwei Liu, Bo Wang, Zhibo Shan, Yi-Han Wang, Yuqin Wang, Hualan Chen, Chengjun Li.
      Influenza A virus (IAV) continues to pose serious threats to the global animal industry and public health security. Identification of critical host factors engaged in the life cycle of IAV and elucidation of the underlying mechanisms of their action are particularly important for the discovery of potential new targets for the development of anti-influenza drugs. Herein, we identified Hydroxyacyl-CoA Dehydratase 3 (HACD3) as a new host factor that supports the replication of IAV. Downregulating the expression of HACD3 reduced the level of viral PB1 protein in IAV-infected cells and in cells that were transiently transfected to express PB1. Silencing HACD3 expression had no effect on the level of PB1 mRNA but could promote the lysosome-mediated autophagic degradation of PB1 protein. Further investigation revealed that HACD3 interacted with PB1 and selective autophagic receptor SQSTM1/p62, and HACD3 competed with SQSTM1/p62 for the interaction with PB1, which prevented PB1 from SQSTM1/p62-mediated autophagic degradation. Collectively, these findings establish that HACD3 plays a positive regulatory role in IAV replication by stabilizing the viral PB1 protein.
    Keywords:  HACD3; PB1; autophagy; influenza A virus; replication
    DOI:  https://doi.org/10.3390/v16050702
  80. Amino Acids. 2024 May 21. 56(1): 36
    Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis.
    Wen Xu, Bo Xie, Dongfan Wei, Xiuzu Song.
      In the initial stages of Alopecia Areata (AA), the predominance of hair breakage or exclamation mark hairs serves as vital indicators of disease activity. These signs are non-invasive and are commonly employed in dermatoscopic examinations. Despite their clinical salience, the underlying etiology precipitating this hair breakage remains largely uncharted territory. Our exhaustive review of the existing literature points to a pivotal role for cysteine-a key amino acid central to hair growth-in these mechanisms. This review will probe and deliberate upon the implications of aberrant cysteine metabolism in the pathogenesis of AA. It will examine the potential intersections of cysteine metabolism with autophagy, ferroptosis, immunity, and psychiatric manifestations associated with AA. Such exploration could illuminate new facets of the disease's pathophysiology, potentially paving the way for innovative therapeutic strategies.
    Keywords:  Alopecia areata; Cysteine metabolism; Exclamation mark hairs; Ferroptosis; Hair breakage
    DOI:  https://doi.org/10.1007/s00726-024-03395-5
  81. Curr Opin Pharmacol. 2024 May 23. pii: S1471-4892(24)00033-X. [Epub ahead of print]76 102463
    Pharmaceutical therapies targeting autophagy for the treatment of age-related macular degeneration.
    Kirstan A Vessey, Andrew I Jobling, Ursula Greferath, Erica L Fletcher.
      Age-related macular degeneration (AMD) is a major cause of irreversible vision loss in the elderly. Although new therapies have recently emerged, there are currently no ways of preventing the development of the disease. Changes in intracellular recycling processes. Changes in intracellular recycling processes, called autophagy, lead to debris accumulation and cellular dysfunction in AMD models and AMD patients. Drugs that enhance autophagy hold promise as therapies for slowing AMD progression in preclinical models; however, more studies in humans are required. While a definitive cure for AMD will likely hinge on a personalized medicine approach, treatments that enhance autophagy hold promise for slowing vision loss.
    DOI:  https://doi.org/10.1016/j.coph.2024.102463
  82. Mol Cancer Res. 2024 May 23.
    Crizotinib enhances PARP inhibitor efficacy in ovarian cancer cells and xenograft models by inducing autophagy.
    Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu.
      Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy. Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0680
  83. Cell Death Differ. 2024 May 23.
    MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
    Xianjun Yu, Mengyuan Feng, Jian Guo, Haoyu Wang, Jun Yu, Anjie Zhang, Jingyi Wu, Yamei Han, Zequn Sun, Yingying Liao, Qun Zhao.
      The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL plays a key role in liver disease. However, how MLKL contributes to hepatocarcinogenesis has not been fully elucidated. Herein, we report that MLKL is upregulated in a diethylnitrosamine (DEN)-induced murine HCC model and is associated with human hepatocellular carcinomas. Hepatocyte-specific MLKL knockout suppresses the progression of hepatocarcinogenesis. Conversely, MLKL overexpression aggravates the initiation and progression of DEN-induced HCC. Mechanistic study reveals that deletion of MLKL significantly increases the activation of autophagy, thereby protecting against hepatocarcinogenesis. MLKL directly interacts with AMPKα1 and inhibits its activity independent of its necroptotic function. Mechanistically, MLKL serves as a bridging molecule between AMPKα1 and protein phosphatase 1B (PPM1B), thus enhancing the dephosphorylation of AMPKα1. Consistently, MLKL expression correlates negatively with AMPKα1 phosphorylation in HCC patients. Taken together, our findings highlight MLKL as a novel AMPK gatekeeper that plays key roles in inhibiting autophagy and driving hepatocarcinogenesis, suggesting that the MLKL-AMPKα1 axis is a potential therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41418-024-01314-5
  84. Nat Commun. 2024 May 18. 15(1): 4237
    Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.
    Xiaoyan Xu, Tingxue Xie, Mengxin Zhou, Yaqin Sun, Fengqi Wang, Yanan Tian, Ziyan Chen, Yanqi Xie, Ronghai Wu, Xufeng Cen, Jichun Zhou, Tingjun Hou, Lei Zhang, Chaoyang Huang, Qingwei Zhao, Dongrui Wang, Hongguang Xia.
      Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-48597-3
  85. Cells. 2024 May 09. pii: 806. [Epub ahead of print]13(10):
    Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer.
    Alyssa N Ho, Violet A Kiesel, Claire E Gates, Bennett H Brosnan, Scott P Connelly, Elaine M Glenny, Alyssa J Cozzo, Stephen D Hursting, Michael Francis Coleman.
      Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.
    Keywords:  autophagy; chemotherapy; combination therapy; insulin receptor/insulin-like growth factor 1 receptor; lysosomes; metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cells13100806
  86. PLoS Biol. 2024 May;22(5): e3002550
    Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.
    Ying Wang, Tianzi Wei, Man Zhao, Aima Huang, Fan Sun, Lu Chen, Risheng Lin, Yubao Xie, Ming Zhang, Shiyu Xu, Zhihui Sun, Liang Hong, Rui Wang, Ruilin Tian, Guofeng Li.
      Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.
    DOI:  https://doi.org/10.1371/journal.pbio.3002550
  87. Biophys Rep. 2024 Apr 30. 10(2): 82-101
    Detection of ribophagy in yeast and mammals.
    Miao Ye, Yuting Chen, Zhaojie Liu, Yigang Wang, Cong Yi.
      Ribophagy, the cellular process wherein ribosomes are selectively self-digested through autophagy, plays a pivotal role in maintaining ribosome turnover. Understanding the molecular regulatory mechanisms governing ribophagy is pivotal to uncover its significance. Consequently, the establishment of methods for detecting ribophagy becomes important. In this protocol, we have optimized, enriched, and advanced existing ribophagy detection techniques, including immunoblotting, fluorescence microscopy, and transmission electron microscopy (TEM), to precisely monitor and quantify ribophagic events. Particularly noteworthy is the introduction of TEM technology for yeast ribophagy detection. In summary, the delineated methods are applicable for detecting ribophagy in both yeast and mammals, laying a solid foundation for further exploring the physiological importance of ribophagy and its potential implications in diverse cellular environments.
    Keywords:  Fluorescence microscopy; Immunoblotting; Ribophagy; Ribosome turnover; Transmission electron microscopy; Yeast and mammals
    DOI:  https://doi.org/10.52601/bpr.2024.240002
  88. Immunity. 2024 May 12. pii: S1074-7613(24)00228-0. [Epub ahead of print]
    Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.
    Xin Li, Weili Sun, Mengxing Huang, Liying Gong, Xiaochen Zhang, Li Zhong, Virginie Calderon, Zhenhua Bian, Yi He, Woong-Kyung Suh, Yang Li, Tengfei Song, Yongrui Zou, Zhe-Xiong Lian, Hua Gu.
      Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.
    Keywords:  BCL6; CBL family proteins; CMA; ICOS; SLE; Tfh; chaperone-mediated autophagy; follicular helper T cell; systemic lupus erythematosus; ubiquitination
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.023
  89. Geroscience. 2024 May 18.
    Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis.
    Jack Donato Rockhold, Heather Marszalkowski, Marco Sannella, Kaleigh Gibney, Lyanne Murphy, Emelia Zukowski, Gabriella H Kalantar, Sara SantaCruz-Calvo, Samantha N Hart, Madison K Kuhn, Jingting Yu, Olivia Stefanik, Gabrielle Chase, Elizabeth A Proctor, Hatice Hasturk, Barbara S Nikolajczyk, Leena P Bharath.
      Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01 µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus's ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug's ability to restore multiple cellular homeostasis mechanisms.
    Keywords:  Autophagy; CD4+ T cells; Everolimus; Inflammaging; NRF2; ROS; Th17 cytokines
    DOI:  https://doi.org/10.1007/s11357-024-01187-z
  90. Biochem Biophys Res Commun. 2024 May 16. pii: S0006-291X(24)00654-5. [Epub ahead of print]720 150118
    Tectorigenin improves metabolic dysfunction-associated steatohepatitis by down-regulating tRF-3040b and promoting mitophagy to inhibit pyroptosis pathway.
    Juanjuan Zhu, Wenmin Tang, Xian Wu, Mao Mu, Quan Zhang, Xueke Zhao.
      Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
    Keywords:  Metabolic dysfunction-associated steatohepatitis; Mitophagy; Pyroptosis; Tectorigenin; tRNA-derived RNA fragments
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150118
  91. Sci Rep. 2024 05 22. 14(1): 11718
    Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice.
    Andrey V Cybulsky, Joan Papillon, Julie Guillemette, José R Navarro-Betancourt, Chen-Fang Chung, Takao Iwawaki, I George Fantus.
      Protein misfolding in the endoplasmic reticulum (ER) of podocytes contributes to the pathogenesis of glomerular diseases. Protein misfolding activates the unfolded protein response (UPR), a compensatory signaling network. We address the role of the UPR and the UPR transducer, inositol-requiring enzyme 1α (IRE1α), in streptozotocin-induced diabetic nephropathy in mice. Diabetes caused progressive albuminuria in control mice that was exacerbated in podocyte-specific IRE1α knockout (KO) mice. Compared to diabetic controls, diabetic IRE1α KO mice showed reductions in podocyte number and synaptopodin. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; the major changes included widening of podocyte foot processes and glomerular basement membrane. Activation of the UPR and autophagy was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD-Glom database demonstrated induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Thus, mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy and attenuation of the glomerular UPR and autophagy, implying a protective effect of IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.
    Keywords:  Albuminuria; Autophagy; Endoplasmic reticulum; Gene expression; Glomerulopathy; Unfolded protein response
    DOI:  https://doi.org/10.1038/s41598-024-62599-7
  92. Cell Biochem Biophys. 2024 May 24.
    AGC1-mediated Metabolic Reprogramming and Autophagy Sustain Survival of Hepatocellular Carcinoma Cells under Glutamine Deprivation.
    Yan Liu, Zeyu Miao, Qing Yang.
      The dependence of hepatocellular carcinoma (HCC) cells on glutamine suggests the feasibility of targeting glutamine metabolism for therapy. However, drugs inhibiting glutamine uptake and breakdown have not shown promising outcomes. Therefore, investigating the mechanism of glutamine metabolism reprogramming in HCC cells is crucial. We used bioinformatics approaches to investigate the metabolic flux of glutamine in HCC cells and validated it using qRT-PCR and western blotting. HCC cells were cultured in glutamine-deprived medium, and changes in glutamate and ATP levels were monitored. Western blotting was employed to assess the expression of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and autophagy-related proteins. The impact of Solute carrier family 25 member 12 (AGC1) on HCC cell proliferation was studied using CCK-8 and colony formation assays. Furthermore, the effects of AGC1 knockdown via siRNA on metabolic reprogramming and energy supply during glutamine deprivation in HCC were explored. During glutamine deprivation, HCC cells sustain cytosolic asparagine synthesis and ATP production through AGC1. Low ATP levels activate AMPK and inhibit mTOR activation, inducing autophagy to rescue HCC cell survival. Knockdown of AGC1 inhibits mitochondrial aspartate output and continuously activates autophagy, rendering HCC cells more sensitive to glutamine deprivation. AGC1 serves as a critical node in the reprogramming of glutamine metabolism and energy supply in HCC cells. This study provides theoretical support for overcoming resistance to drugs targeting glutamine metabolism.
    Keywords:  AGC1; Autophagy; Glutamine deprivation; Hepatocellular carcinoma; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s12013-024-01311-y
  93. Cell Commun Signal. 2024 May 24. 22(1): 285
    Molecular mechanisms of aging and anti-aging strategies.
    Yumeng Li, Xutong Tian, Juyue Luo, Tongtong Bao, Shujin Wang, Xin Wu.
      Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.
    Keywords:  Aging; Aging triggers; Anti-aging strategies; Senolytic; Synthetic
    DOI:  https://doi.org/10.1186/s12964-024-01663-1
  94. Acta Biochim Biophys Sin (Shanghai). 2024 May 22.
    Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.
    Andi Wang, Zhuo Li, Dan Zhang, Chang Chen, Hua Zhang.
      Autophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.
    Keywords:  endoplasmic reticulum autophagy (ER-phagy); lipidomic metabolome; mitochondria-associated endoplasmic reticulum membrane; mitochondrial dysfunction; preeclampsia
    DOI:  https://doi.org/10.3724/abbs.2024065
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