bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–04–14
eighty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. The autophagy inhibitor NSC185058 suppresses mTORC1-mediated protein anabolism in cultured skeletal muscle.
  2. Rag-GTPase-TFEB/TFE3 axis controls B cell mitochondrial fitness and humoral immunity independent of mTORC1.
  3. The Endo-Lysosomal Damage Response.
  4. ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism.
  5. Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons.
  6. Massive ER protein disposal by reticulophagy receptors and selective disposal by TOLLIP.
  7. The molecular mechanisms regulating the assembly of the autophagy initiation complex.
  8. Transformation of autophagic SQSTM1 droplets to SQSTM1-dependent P-bodies.
  9. Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
  10. Autophagy Regulates Esophageal Epithelial Renewal.
  11. Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling.
  12. The role of autophagy in odontogenesis, dental implant surgery, periapical and periodontal diseases.
  13. Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells.
  14. Autophagy receptor ZmNBR1 promotes the autophagic degradation of ZmBRI1a and enhances drought tolerance in maize.
  15. MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
  16. Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.
  17. Role of Sphingosine Kinase 1 in Glucolipotoxicity-Induced Early Activation of Autophagy in INS-1 Pancreatic β Cells.
  18. Mechanisms and Implications of Podocyte Autophagy in Chronic Kidney Disease.
  19. COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites.
  20. SS-31 inhibits the inflammatory response by increasing ATG5 and promoting autophagy in lipopolysaccharide-stimulated HepG2 cells.
  21. Autophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage.
  22. Elevated α-synuclein levels inhibit mitophagic flux.
  23. The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues.
  24. The autophagy-mediated mechanism via TSC1/mTOR signaling pathway in thiram-induced tibial dyschondroplasia of broilers.
  25. Endogenous S100P-mediated autophagy regulates the chemosensitivity of leukemia cells through the p53/AMPK/mTOR pathway.
  26. Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.
  27. GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy.
  28. UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.
  29. Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions.
  30. Relationship of mTORC1 and ferroptosis in tumors.
  31. Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity.
  32. Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review).
  33. Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.
  34. Csn5 inhibits autophagy by regulating the ubiquitination of Atg6 and Tor to mediate the pathogenicity of Magnaporthe oryzae.
  35. Regulation of translation in response to iron deficiency in human cells.
  36. TFEB overexpression through GFAP promoter disrupts neuronal lamination by dysregulating neurogenesis during embryonic development.
  37. Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing.
  38. Decoding the Versatile Landscape of Autophagic Protein VMP1 in Cancer: A Comprehensive Review across Tissue Types and Regulatory Mechanisms.
  39. Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapetuics.
  40. Novel combinatorial autophagy inhibition therapy for triple negative breast cancers.
  41. Identification of autophagy receptors for the Crohn's disease-associated adherent-invasive Escherichia coli.
  42. Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population.
  43. Optimizing myocardial cell protection with xanthine derivative KMUP-3 potentiates autophagy through the PI3K/Akt/eNOS axis.
  44. The Role of Autophagy in Erectile Dysfunction.
  45. WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.
  46. PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
  47. Role of autophagy in ischemic stroke: insights from animal models and preliminary evidence in the human disease.
  48. Impairment of the glial phagolysosomal system drives prion-like propagation in a Drosophila model of Huntington's disease.
  49. Degradation of hexosylceramides is required for timely corpse clearance via formation of cargo-containing phagolysosomal vesicles.
  50. Metformin Mitigates Adipogenesis of Fibro-adipogenic Progenitors After Rotator Cuff Tears Via Activating mTOR/ULK1 Mediated Autophagy.
  51. Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy.
  52. The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation.
  53. 6PPDQ induces cardiomyocyte senescence via AhR/ROS-mediated autophagic flux blockage.
  54. Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.
  55. Alcohol-induced Golgiphagy is triggered by the downregulation of Golgi GTPase RAB3D.
  56. Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration.
  57. Regulated cell death and its role in Alzheimer's disease and amyotrophic lateral sclerosis.
  58. Atg5 deficiency in macrophages protects against kidney fibrosis via the CCR6-CCL20 axis.
  59. Versatile Fluorescence Lifetime-Based Copper Probe to Quantify Mitochondrial Membrane Potential and Reveal Its Interaction with Protein Aggregation.
  60. Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2.
  61. TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
  62. Activating transcription factor 4: a regulator of stress response in human cancers.
  63. Crosstalk between autophagy and ferroptosis mediate injury in ischemic stroke by generating reactive oxygen species.
  64. DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
  65. The ZIKV NS5 Protein Aberrantly Alters the Tubulin Cytoskeleton, Induces the Accumulation of Autophagic p62 and Affects IFN Production: HDAC6 Has Emerged as an Anti-NS5/ZIKV Factor.
  66. XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer.
  67. Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases.
  68. Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.
  69. Alterations in Proteostasis Mechanisms in Niemann-Pick Type C Disease.
  70. STAM2 negatively regulates the MyD88-mediated NF-κB signaling pathway in miiuy croaker, Miichthys miiuy.
  71. S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
  72. Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights.
  73. Dynamic changes in lysosome-related pathways in APP/PS1 mice with aging.
  74. Nutrient deprivation induces mouse embryonic diapause mediated by Gator1 and Tsc2.
  75. Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment.
  76. The Intricate Balance between Life and Death: ROS, Cathepsins, and Their Interplay in Cell Death and Autophagy.
  77. C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity.
  78. Key genes and convergent pathogenic mechanisms in Parkinson disease.
  79. Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.
  80. Galectin-3 and Autophagy in Renal Acute Tubular Necrosis.
  81. Proxies introduce bias in decoding TORC1 activity.
  82. Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan.
  1. Sci Rep. 2024 04 06. 14(1): 8094
    The autophagy inhibitor NSC185058 suppresses mTORC1-mediated protein anabolism in cultured skeletal muscle.
    Patrick J Ryan, Selina Uranga, Sean T Stanelle, Megan H Lewis, Colleen L O'Reilly, Jessica M Cardin, J William Deaver, Aaron B Morton, James D Fluckey.
      The mammalian target of rapamycin (mTOR), and specifically the mTOR complex 1 (mTORC1) is the central regulator of anabolism in skeletal muscle. Among the many functions of this kinase complex is the inhibition of the catabolic process of autophagy; however, less work has been done in investigating the role of autophagy in regulating mTORC1 signaling. Using an in vitro model to better understand the pathways involved, we activated mTORC1 by several different means (growth factors, leucine supplementation, or muscle contraction), alone or with the autophagy inhibitor NSC185058. We found that inhibiting autophagy with NSC185058 suppresses mTORC1 activity, preventing any increase in cellular protein anabolism. These decrements were the direct result of action on the mTORC1 kinase, which we demonstrate, for the first time, cannot function when autophagy is inhibited by NSC185058. Our results indicate that, far from being a matter of unidirectional action, the relationship between mTORC1 and the autophagic cascade is more nuanced, with autophagy serving as an mTORC1 input, and mTORC1 inhibition of autophagy as a form of homeostatic feedback to regulate anabolic signaling. Future studies of cellular metabolism will have to consider this fundamental intertwining of protein anabolism and catabolism, and how it ultimately serves to regulate muscle proteostasis.
    DOI:  https://doi.org/10.1038/s41598-024-58716-1
  2. Res Sq. 2024 Mar 29. pii: rs.3.rs-3957355. [Epub ahead of print]
    Rag-GTPase-TFEB/TFE3 axis controls B cell mitochondrial fitness and humoral immunity independent of mTORC1.
    Hu Zeng, Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens Watzlawik, Yin Chen, Ariel Raybuck, Daniel Billadeau, Virginia Shapiro, Wolfdieter Springer, Sun Jie, Mark Boothby.
      During the humoral immune response, B cells undergo rapid metabolic reprogramming with a high demand for nutrients, which are vital to sustain the formation of the germinal centers (GCs). Rag-GTPases sense amino acid availability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway and suppress transcription factor EB (TFEB) and transcription factor enhancer 3 (TFE3), members of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, how Rag-GTPases coordinate amino acid sensing, mTORC1 activation, and TFEB/TFE3 activity in humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and generate plasmablasts in both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish Rag-GTPase-TFEB/TFE3 axis as an mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.
    DOI:  https://doi.org/10.21203/rs.3.rs-3957355/v1
  3. Annu Rev Biochem. 2024 Apr 09.
    The Endo-Lysosomal Damage Response.
    Hemmo Meyer, Bojana Kravic.
      Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity of the lysosomal membrane. If repair fails or if damage is too extensive, lysosomes are isolated and degraded by a form of selective autophagy termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis and regeneration of new lysosomal components to reestablish the full lysosomal capacity of the cell. This damage response is vital to counteract the effects of various conditions, including neurodegeneration and infection, and can constitute a critical vulnerability in cancer cells.
    DOI:  https://doi.org/10.1146/annurev-biochem-030222-102505
  4. Traffic. 2024 Apr;25(4): e12933
    ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism.
    Kevin Ostacolo, Adrián López García de Lomana, Clémence Larat, Valgerdur Hjaltalin, Kristrun Yr Holm, Sigríður S Hlynsdóttir, Margaret Soucheray, Linda Sooman, Ottar Rolfsson, Nevan J Krogan, Eirikur Steingrimsson, Danielle L Swaney, Margret H Ogmundsdottir.
      Macroautophagy/autophagy is an essential catabolic process that targets a wide variety of cellular components including proteins, organelles, and pathogens. ATG7, a protein involved in the autophagy process, plays a crucial role in maintaining cellular homeostasis and can contribute to the development of diseases such as cancer. ATG7 initiates autophagy by facilitating the lipidation of the ATG8 proteins in the growing autophagosome membrane. The noncanonical isoform ATG7(2) is unable to perform ATG8 lipidation; however, its cellular regulation and function are unknown. Here, we uncovered a distinct regulation and function of ATG7(2) in contrast with ATG7(1), the canonical isoform. First, affinity-purification mass spectrometry analysis revealed that ATG7(2) establishes direct protein-protein interactions (PPIs) with metabolic proteins, whereas ATG7(1) primarily interacts with autophagy machinery proteins. Furthermore, we identified that ATG7(2) mediates a decrease in metabolic activity, highlighting a novel splice-dependent function of this important autophagy protein. Then, we found a divergent expression pattern of ATG7(1) and ATG7(2) across human tissues. Conclusively, our work uncovers the divergent patterns of expression, protein interactions, and function of ATG7(2) in contrast to ATG7(1). These findings suggest a molecular switch between main catabolic processes through isoform-dependent expression of a key autophagy gene.
    Keywords:  ATG7; ATG7(2); GTEx; PPI; autophagy; glycolysis; isoforms; lipidation; mitochondrial activity
    DOI:  https://doi.org/10.1111/tra.12933
  5. Nat Commun. 2024 Apr 10. 15(1): 3113
    Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons.
    Xiaoting Zhou, You-Kyung Lee, Xianting Li, Henry Kim, Carlos Sanchez-Priego, Xian Han, Haiyan Tan, Suiping Zhou, Yingxue Fu, Kerry Purtell, Qian Wang, Gay R Holstein, Beisha Tang, Junmin Peng, Nan Yang, Zhenyu Yue.
      Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.
    DOI:  https://doi.org/10.1038/s41467-024-47440-z
  6. Autophagy. 2024 Apr 11. 1-2
    Massive ER protein disposal by reticulophagy receptors and selective disposal by TOLLIP.
    Yuki Hayashi, Hidenori Ichijo.
      Proteostasis of the endoplasmic reticulum (ER) is maintained by coordinated action of two major catabolic pathways: proteasome-dependent ER-associated degradation (ERAD) and less characterized lysosomal pathways. Recent studies on ER-specific autophagy (termed "reticulophagy") have highlighted the importance of lysosomes for ER proteostasis. Key to this process are proteins termed reticulophagy receptors that connect ER fragments and Atg8-family proteins, facilitating the lysosomal degradation of both native and aberrant ER proteins in a relatively nonselective manner. In contrast, our recent work identified TOLLIP as a novel type of cargo receptor specifically dedicated to the lysosomal degradation of aberrant ER membrane proteins. The clients of TOLLIP include an engineered model substrate, which mimics an ER-retained aberrant membrane protein, and motor neuron disease-linked misfolded mutants of VAPB and BSCL2/Seipin. TOLLIP acts as a receptor to connect these aberrant ER membrane proteins and phosphatidylinositol-3-phosphate (PtdIns3P) by recognizing the former through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain, and the latter through its C2 domain. These interactions enable PtdIns3P-dependent vesicular trafficking of aberrant membrane proteins to lysosomes without promoting reticulophagic turnover of bulk ER.
    Keywords:  ER stress; ER-phagy; ERAD; TOLLIP; motor neuron disease; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340417
  7. Bioessays. 2024 Apr 09. e2300243
    The molecular mechanisms regulating the assembly of the autophagy initiation complex.
    Weijing Yao, Yuyao Feng, Yi Zhang, Huan Yang, Cong Yi.
      The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy-related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex through multiple regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification.
    Keywords:  PAS; Ypt1; autophagy initiation complex; regulatory mechanism; signaling molecules
    DOI:  https://doi.org/10.1002/bies.202300243
  8. Autophagy. 2024 Apr 10. 1-2
    Transformation of autophagic SQSTM1 droplets to SQSTM1-dependent P-bodies.
    Evelina Valionyte, Elizabeth R Barrow, Chris R Baxter, Sharon Herath, Shouqing Luo.
      SQSTM1/p62 droplets play crucial roles in droplets-based macroautophagy/autophagy including selective autophagy and bulk autophagy. We observed that under several stress milieus, SQSTM1 droplets entirely colocalize with P-body markers, and these stress-induced SQSTM1 droplets contain mRNAs. We thus determined that under certain stress conditions, autophagic SQSTM1 droplets are converted to a type of enlarged P-bodies, designated SQSTM1/p62-dependent P-bodies (pd-PBs). Stress-enhanced SQSTM1 droplet formation drives the nucleation of pd-PBs through the interaction between SQSTM1 and the RNA-binding protein DDX6. Furthermore, pd-PBs sequester PYCARD, facilitating the assembly of NLRP3 inflammasomes, and in turn induce inflammation-related cytotoxicity. Our study suggests that under stress settings, autophagic SQSTM1 droplets are transformed to pd-PBs, underlining a critical role of SQSTM1 in P-body condensation.
    Keywords:  Autophagy; NLRP3 inflammasome; P-bodies; PYCARD; SQSTM1
    DOI:  https://doi.org/10.1080/15548627.2024.2340413
  9. Mol Neurobiol. 2024 Apr 06.
    Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.
    Sarah Hui, Jimmy George, Minesh Kapadia, Hien Chau, Zahn Bariring, Rebecca Earnshaw, Kashfia Shafiq, Lorraine V Kalia, Suneil K Kalia.
      Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.
    Keywords:  Alpha-synuclein; Lysosomes; Mitochondria dysfunction; Mitophagy; Neurodegeneration; Parkinson’s disease; Substantia nigra pars compacta
    DOI:  https://doi.org/10.1007/s12035-024-04131-6
  10. Cell Mol Gastroenterol Hepatol. 2024 Apr 04. pii: S2352-345X(24)00060-2. [Epub ahead of print]
    Autophagy Regulates Esophageal Epithelial Renewal.
    Yash Choksi.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.03.008
  11. Proc Natl Acad Sci U S A. 2024 Apr 16. 121(16): e2315958121
    Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling.
    Yen-Ching Chang, Yuan Gao, Joo Yeun Lee, Yi-Jheng Peng, Jennifer Langen, Karen T Chang.
      The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood, as neurodevelopment and structural plasticity are tightly linked. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity and synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We report that while both synapse development and activity-induced synaptic remodeling at the fly NMJ require macroautophagy (hereafter referred to as autophagy), bifurcation in the autophagy pathway differentially impacts development and synaptic plasticity. We demonstrate that neuronal activity enhances autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity.
    Keywords:  Drosophila; autophagy; neuromuscular junction; synaptic plasticity; synaptic remodeling
    DOI:  https://doi.org/10.1073/pnas.2315958121
  12. J Cell Mol Med. 2024 Apr;28(8): e18297
    The role of autophagy in odontogenesis, dental implant surgery, periapical and periodontal diseases.
    Sevinç İnan, Emre Barış.
      Autophagy is a cellular process that is evolutionarily conserved, involving the sequestration of damaged organelles and proteins into autophagic vesicles, which subsequently fuse with lysosomes for degradation. Autophagy controls the development of many diseases by influencing apoptosis, inflammation, the immune response and different cellular processes. Autophagy plays a significant role in the aetiology of disorders associated with dentistry. Autophagy controls odontogenesis. Furthermore, it is implicated in the pathophysiology of pulpitis and periapical disorders. It enhances the survival, penetration and colonization of periodontal pathogenic bacteria into the host periodontal tissues and facilitates their escape from host defences. Autophagy plays a crucial role in mitigating exaggerated inflammatory reactions within the host's system during instances of infection and inflammation. Autophagy also plays a role in the relationship between periodontal disease and systemic diseases. Autophagy promotes wound healing and may enhance implant osseointegration. This study reviews autophagy's dento-alveolar effects, focusing on its role in odontogenesis, periapical diseases, periodontal diseases and dental implant surgery, providing valuable insights for dentists on tooth development and dental applications. A thorough examination of autophagy has the potential to discover novel and efficacious treatment targets within the field of dentistry.
    Keywords:  ATG; dentistry; inflammation; pathogenesis; tooth
    DOI:  https://doi.org/10.1111/jcmm.18297
  13. Methods Mol Biol. 2024 Apr 13.
    Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells.
    Javad Alizadeh, Simone C da Silva Rosa, Marco Cordani, Saeid Ghavami.
      Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer characterized by its aggressive nature and high mortality rate, primarily due to late-stage diagnosis and metastatic spread. Recent studies underscore the pivotal role of mitophagy, a selective form of autophagy targeting damaged or superfluous mitochondria, in cancer biology, including NSCLC. Mitophagy regulation may influence cancer cell survival, proliferation, and metastasis by modulating mitochondrial quality and cellular energy homeostasis. Herein, we present a comprehensive methodology developed in our laboratory for the evaluation of mitophagy in NSCLC tumor cells. Utilizing a combination of immunoblotting, immunocytochemistry, and fluorescent microscopy, we detail the steps to quantify early and late mitophagy markers and mitochondrial dynamics. Our findings highlight the potential of targeting mitophagy pathways as a novel therapeutic strategy in NSCLC, offering insights into the complex interplay between mitochondrial dysfunction and tumor progression. This study not only sheds light on the significance of mitophagy in NSCLC but also establishes a foundational approach for its investigation, paving way for future research in this critical area of cancer biology.
    Keywords:  Autophagy; Cellular homeostasis; Mitochondrial dynamics; Mitophagy; Non-small cell adenocarcinoma
    DOI:  https://doi.org/10.1007/7651_2024_532
  14. J Integr Plant Biol. 2024 Apr 12.
    Autophagy receptor ZmNBR1 promotes the autophagic degradation of ZmBRI1a and enhances drought tolerance in maize.
    Yang Xiang, Guangdong Li, Qian Li, Yingxue Niu, Yitian Pan, Yuan Cheng, Xiangli Bian, Chongyang Zhao, Yuanhong Wang, Aying Zhang.
      Drought stress is a crucial environmental factor that limits plant growth, development, and productivity. Autophagy of misfolded proteins can help alleviate the damage caused in plants experiencing drought. However, the mechanism of autophagy-mediated drought tolerance in plants remains largely unknown. Here, we cloned the gene for a maize (Zea mays) selective autophagy receptor, NEXT TO BRCA1 GENE 1 (ZmNBR1), and identified its role in the response to drought stress. We observed that drought stress increased the accumulation of autophagosomes. RNA sequencing and reverse transcription-quantitative polymerase chain reaction showed that ZmNBR1 is markedly induced by drought stress. ZmNBR1 overexpression enhanced drought tolerance, while its knockdown reduced drought tolerance in maize. Our results established that ZmNBR1 mediates the increase in autophagosomes and autophagic activity under drought stress. ZmNBR1 also affects the expression of genes related to autophagy under drought stress. Moreover, we determined that BRASSINOSTEROID INSENSITIVE 1A (ZmBRI1a), a brassinosteroid receptor of the BRI1-like family, interacts with ZmNBR1. Phenotype analysis showed that ZmBRI1a negatively regulates drought tolerance in maize, and genetic analysis indicated that ZmNBR1 acts upstream of ZmBRI1a in regulating drought tolerance. Furthermore, ZmNBR1 facilitates the autophagic degradation of ZmBRI1a under drought stress. Taken together, our results reveal that ZmNBR1 regulates the expression of autophagy-related genes, thereby increasing autophagic activity and promoting the autophagic degradation of ZmBRI1a under drought stress, thus enhancing drought tolerance in maize. These findings provide new insights into the autophagy degradation of brassinosteroid signaling components by the autophagy receptor NBR1 under drought stress.
    Keywords:  Zea mays; ZmBRI1a; ZmNBR1; autophagy receptor; drought tolerance
    DOI:  https://doi.org/10.1111/jipb.13662
  15. Autophagy. 2024 Apr 10.
    MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
    Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.
      Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.
    Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340399
  16. Biochem Biophys Rep. 2024 Jul;38 101705
    Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.
    Yoshinori Tanaka, Lina Kozuma, Hirotsugu Hino, Kosuke Takeya, Masumi Eto.
      (Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.
    Keywords:  Abemaciclib; Autophagic flux; PI(3)P; TDP-43; Vacuolin-1
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101705
  17. Cells. 2024 Apr 05. pii: 636. [Epub ahead of print]13(7):
    Role of Sphingosine Kinase 1 in Glucolipotoxicity-Induced Early Activation of Autophagy in INS-1 Pancreatic β Cells.
    Nicolas Coant, Karima Rendja, Lara Bellini, Mélissa Flamment, Jeannine Lherminier, Bernard Portha, Patrice Codogno, Hervé Le Stunff.
      Insulin-producing pancreatic β cells play a crucial role in the regulation of glucose homeostasis, and their failure is a key event for diabetes development. Prolonged exposure to palmitate in the presence of elevated glucose levels, termed gluco-lipotoxicity, is known to induce β cell apoptosis. Autophagy has been proposed to be regulated by gluco-lipotoxicity in order to favor β cell survival. However, the role of palmitate metabolism in gluco-lipotoxcity-induced autophagy is presently unknown. We therefore treated INS-1 cells for 6 and 24 h with palmitate in the presence of low and high glucose concentrations and then monitored autophagy. Gluco-lipotoxicity induces accumulation of LC3-II levels in INS-1 at 6 h which returns to basal levels at 24 h. Using the RFP-GFP-LC3 probe, gluco-lipotoxicity increased both autophagosomes and autolysosmes structures, reflecting early stimulation of an autophagy flux. Triacsin C, a potent inhibitor of the long fatty acid acetyl-coA synthase, completely prevents LC3-II formation and recruitment to autophagosomes, suggesting that autophagic response requires palmitate metabolism. In contrast, etomoxir and bromo-palmitate, inhibitors of fatty acid mitochondrial β-oxidation, are unable to prevent gluco-lipotoxicity-induced LC3-II accumulation and recruitment to autophagosomes. Moreover, bromo-palmitate and etomoxir potentiate palmitate autophagic response. Even if gluco-lipotoxicity raised ceramide levels in INS-1 cells, ceramide synthase 4 overexpression does not potentiate LC3-II accumulation. Gluco-lipotoxicity also still stimulates an autophagic flux in the presence of an ER stress repressor. Finally, selective inhibition of sphingosine kinase 1 (SphK1) activity precludes gluco-lipotoxicity to induce LC3-II accumulation. Moreover, SphK1 overexpression potentiates autophagic flux induced by gluco-lipotxicity. Altogether, our results indicate that early activation of autophagy by gluco-lipotoxicity is mediated by SphK1, which plays a protective role in β cells.
    Keywords:  autophagy; cell death; ceramides; gluco-lipotoxicity; pancreatic β cells; sphingosine kinase 1; sphingosine-1-phosphate; type 2 diabetes
    DOI:  https://doi.org/10.3390/cells13070636
  18. Am J Physiol Renal Physiol. 2024 Apr 11.
    Mechanisms and Implications of Podocyte Autophagy in Chronic Kidney Disease.
    Rachel Njeim, Sandra Merscher, Alessia Fornoni.
      Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease. In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions.
    Keywords:  Autophagy; Chronic Kidney Disease; Podocyte Injury
    DOI:  https://doi.org/10.1152/ajprenal.00415.2023
  19. Dev Cell. 2024 Apr 06. pii: S1534-5807(24)00195-3. [Epub ahead of print]
    COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites.
    Ya-Cheng Liao, Song Pang, Wei-Ping Li, Gleb Shtengel, Heejun Choi, Kathy Schaefer, C Shan Xu, Jennifer Lippincott-Schwartz.
      Endoplasmic reticulum exit sites (ERESs) are tubular outgrowths of endoplasmic reticulum that serve as the earliest station for protein sorting and export into the secretory pathway. How these structures respond to different cellular conditions remains unclear. Here, we report that ERESs undergo lysosome-dependent microautophagy when Ca2+ is released by lysosomes in response to nutrient stressors such as mTOR inhibition or amino acid starvation in mammalian cells. Targeting and uptake of ERESs into lysosomes were observed by super-resolution live-cell imaging and focus ion beam scanning electron microscopy (FIB-SEM). The mechanism was ESCRT dependent and required ubiquitinated SEC31, ALG2, and ALIX, with a knockout of ALG2 or function-blocking mutations of ALIX preventing engulfment of ERESs by lysosomes. In vitro, reconstitution of the pathway was possible using lysosomal lipid-mimicking giant unilamellar vesicles and purified recombinant components. Together, these findings demonstrate a pathway of lysosome-dependent ERES microautophagy mediated by COPII, ALG2, and ESCRTS induced by nutrient stress.
    Keywords:  ALG2; COPII; ER exit sites; ESCRTs; FIB-SEM; autophagy; cellular stress; lysosome; mTOR
    DOI:  https://doi.org/10.1016/j.devcel.2024.03.027
  20. Biochem Biophys Res Commun. 2024 Apr 04. pii: S0006-291X(24)00423-6. [Epub ahead of print]710 149887
    SS-31 inhibits the inflammatory response by increasing ATG5 and promoting autophagy in lipopolysaccharide-stimulated HepG2 cells.
    Yunan Mo, Songyun Deng, Yuhang Ai, Wenchao Li.
      SS-31 is a mitochondria-targeting short peptide. Recent studies have indicated its hepatoprotective effects. In our study, we investigated the impact of SS-31 on LPS-induced autophagy in HepG2 cells. The results obtained from a dual-fluorescence autophagy detection system revealed that SS-31 promotes the formation of autolysosomes and autophagosomes, thereby facilitating autophagic flux to a certain degree. Additionally, both ELISA and qPCR analyses provided further evidence that SS-31 safeguards HepG2 cells against inflammatory responses triggered by LPS through ATG5-dependent autophagy. In summary, our study demonstrates that SS-31 inhibits LPS-stimulated inflammation in HepG2 cells by upregulating ATG5-dependent autophagy.
    Keywords:  ATG5; Autophagosomes; Autophagy; Lipopolysaccharide; SS-31
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149887
  21. Exp Eye Res. 2024 Apr 07. pii: S0014-4835(24)00110-6. [Epub ahead of print]242 109889
    Autophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage.
    Zhao Zhang, Fengming Liang, Jun Chang, Xiaoqian Shan, Zhixian Yin, Li Wang, Shujiao Li.
      Dry age-related macular degeneration (AMD) is a prevalent clinical condition that leads to permanent damage to central vision and poses a significant threat to patients' visual health. Although the pathogenesis of dry AMD remains unclear, there is consensus on the role of retinal pigment epithelium (RPE) damage. Oxidative stress and chronic inflammation are major contributors to RPE cell damage, and the NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) inflammasome mediates the inflammatory response leading to apoptosis in RPE cells. Furthermore, lipofuscin accumulation results in oxidative stress, NLRP3 activation, and the development of vitelliform lesions, a hallmark of dry AMD, all of which may contribute to RPE dysfunction. The process of autophagy, involving the encapsulation, recognition, and transport of accumulated proteins and dead cells to the lysosome for degradation, is recognized as a significant pathway for cellular self-protection and homeostasis maintenance. Recently, RPE cell autophagy has been discovered to be closely linked to the development of macular degeneration, positioning autophagy as a cutting-edge research area in the realm of dry AMD. In this review, we present an overview of how lipofuscin, oxidative stress, and the NLRP3 inflammasome damage the RPE through their respective causal mechanisms. We summarized the connection between autophagy, oxidative stress, and NLRP3 inflammatory cytokines. Our findings suggest that targeting autophagy improves RPE function and sustains visual health, offering new perspectives for understanding the pathogenesis and clinical management of dry AMD.
    Keywords:  Autophagy; Dry age-related macular degeneration; Lipofuscin; NLRP3 inflammasome; Oxidative stress; mTOR
    DOI:  https://doi.org/10.1016/j.exer.2024.109889
  22. NPJ Parkinsons Dis. 2024 Apr 09. 10(1): 80
    Elevated α-synuclein levels inhibit mitophagic flux.
    Inge Kinnart, Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Roman Praschberger, Nils Schoovaerts, Catherine Verfaillie, Patrik Verstreken, Wim Vandenberghe.
      The pathogenic effect of SNCA gene multiplications indicates that elevation of wild-type α-synuclein levels is sufficient to cause Parkinson's disease (PD). Mitochondria have been proposed to be a major target of α-synuclein-induced damage. PINK1/parkin/DJ-1-mediated mitophagy is a defense strategy that allows cells to selectively eliminate severely damaged mitochondria. Here, we quantified mitophagic flux and non-mitochondrial autophagic flux in three models of increased α-synuclein expression: 1/Drosophila melanogaster that transgenically express human wild-type and mutant α-synuclein in flight muscle; 2/human skin fibroblasts transfected with α-synuclein or β-synuclein; and 3/human induced pluripotent stem cell (iPSC)-derived neurons carrying an extra copy of wild-type SNCA under control of a doxycycline-inducible promoter, allowing titratable α-synuclein upregulation. In each model, elevated α-synuclein levels potently suppressed mitophagic flux, while non-mitochondrial autophagy was preserved. In human neurons, a twofold increase in wild-type α-synuclein was already sufficient to induce this effect. PINK1 and parkin activation and mitochondrial translocation of DJ-1 after mitochondrial depolarization were not affected by α-synuclein upregulation. Overexpression of the actin-severing protein cofilin or treatment with CK666, an inhibitor of the actin-related protein 2/3 (Arp2/3) complex, rescued mitophagy in neurons with increased α-synuclein, suggesting that excessive actin network stabilization mediated the mitophagy defect. In conclusion, elevated α-synuclein levels inhibit mitophagic flux. Disruption of actin dynamics may play a key role in this effect.
    DOI:  https://doi.org/10.1038/s41531-024-00696-0
  23. Annu Rev Biochem. 2024 Apr 11.
    The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues.
    Uche N Medoh, Monther Abu-Remaileh.
      Lysosomes catabolize and recycle lipids and other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic lipid whose levels are altered across myriad lysosome-associated diseases. Here, we review the discovery of BMP over half a century ago and its structural properties that facilitate the activation of lipid hydrolases and recruitment of their coactivators. We further discuss the current, yet incomplete, understanding of BMP catabolism and anabolism. To conclude, we discuss its role in lysosome-associated diseases and the potential for modulating its levels by pharmacologically activating and inhibiting the BMP synthase to therapeutically target lysosomal storage disorders, drug-induced phospholipidosis, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, cancer, and viral infection.
    DOI:  https://doi.org/10.1146/annurev-biochem-092823-113814
  24. Sci Total Environ. 2024 Apr 07. pii: S0048-9697(24)02448-3. [Epub ahead of print] 172305
    The autophagy-mediated mechanism via TSC1/mTOR signaling pathway in thiram-induced tibial dyschondroplasia of broilers.
    Chuxian Quan, Shimeng Zhou, Yan Zhang, Muhammad Fakhar-E-Alam Kulyar, Saisai Gong, Shah Nawaz, Quan Mo, Jiakui Li.
      Thiram is a member of the dithiocarbamate family and is widely used in agriculture. Its residues lead to various diseases, among which tibial dyschondroplasia (TD) in broiler chickens is the most common. Recent studies have also demonstrated that thiram residues may harm human health. Our previous study showed that the activity of the mTOR (mammalian target of rapamycin) signaling pathway has changed after thiram exposure. In the current study, we investigated the effect of autophagy via the mTOR signaling pathway after thiram exposure in vitro and in vivo. Our results showed that thiram inhibited the protein expression of mTOR signaling pathway-related genes such as p-4EBP1 and p-S6K1. The analysis showed a significant increase in the expression of key autophagy-related proteins, including LC3, ULK1, ATG5, and Beclin1. Further investigation proved that the effects of thiram were mediated through the downregulation of mTOR. The mTOR agonist MHY-1485 could reverse the upregulation of autophagy caused by thiram in vitro. Moreover, using knockdown of TSC1 resulted in chondrocytes expressing lower levels of autophagy. In conclusion, our results demonstrate that thiram promotes autophagy via the mTOR signaling pathway in chondrogenesis, providing a potential pharmacological target for the prevention of TD.
    Keywords:  Autophagy; Chondrocytes; Thiram; Tibial dyschondroplasia; mTOR
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.172305
  25. Am J Cancer Res. 2024 ;14(3): 1121-1138
    Endogenous S100P-mediated autophagy regulates the chemosensitivity of leukemia cells through the p53/AMPK/mTOR pathway.
    Min Peng, Fanghua Ye, Chenying Fan, Jiajia Dong, Wenwen Chai, Wenjun Deng, Hui Zhang, Liangchun Yang.
      Autophagy, a highly regulated lysosome-dependent catabolic pathway, has garnered increasing attention because of its role in leukemia resistance. Among the S100 family of small calcium-binding proteins, S100P is differentially expressed in various tumor cell lines, thereby influencing tumor occurrence, invasion, metastasis, and drug resistance. However, the relationship between S100P and autophagy in determining chemosensitivity in leukemia cells remains unexplored. Our investigation revealed a negative correlation between S100P expression and the clinical status in childhood leukemia, with its presence observed in HL-60 and Jurkat cell lines. Suppression of S100P expression resulted in increased cell proliferation and decreased chemosensitivity in leukemia cells, whereas enhancement of S100P expression inhibited cell proliferation and increased chemosensitivity. Additionally, S100P knockdown drastically promoted autophagy, which was subsequently suppressed by S100P upregulation. Moreover, the p53/AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was found to be functionally associated with S100P-mediated autophagy. Knockdown of S100P expression led to a decrease in p53 and p-mTOR levels and an increase in p-AMPK expression, ultimately promoting autophagy. This effect was reversed by administration of Tenovin-6 (a p53 activator) and Compound C (an AMPK inhibitor). The findings of our in vivo experiments provide additional evidence supporting the aforementioned data. Specifically, S100P inhibition significantly enhanced the growth of HL-60 tumor xenografts and increased the expression of microtubule-associated protein 1 light chain 3 and p-AMPK in nude mice. Consequently, it can be concluded that S100P plays a regulatory role in the chemosensitivity of leukemia cells by modulating the p53/AMPK/mTOR pathway, which controls autophagy in leukemia cells.
    Keywords:  S100P; autophagy; chemosensitivity; leukemia; p53
    DOI:  https://doi.org/10.62347/NWXE8730
  26. Front Immunol. 2024 ;15 1367048
    Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.
    Zhenghui Yang, Xinyi Wang, Tianxiang Dong, Wei-Jia Zhao, Hongbin Li.
       Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect.
    Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics.
    Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time.
    Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.
    Keywords:  Candida glabrata; LC3-associated phagocytosis; autophagy; glucocorticoids; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2024.1367048
  27. Sci Total Environ. 2024 Apr 04. pii: S0048-9697(24)02212-5. [Epub ahead of print] 172069
    GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy.
    Pu Zhao, Quan Yuan, Chen Liang, Yilu Ma, Xiaoying Zhu, Xueqin Hao, Xinyu Li, Jian Shi, Qizhi Fu, Hua Fan, Dongmei Wang.
      Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment.
    Keywords:  Chaperone-mediated autophagy; Cognitive deficits; Ferroptosis; Fluoride; GPX4; MtROS
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.172069
  28. Genetics. 2024 Apr 06. pii: iyae053. [Epub ahead of print]
    UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.
    Cody J Drozd, Tamjid A Chowdhury, Christopher C Quinn.
      In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In C. elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.
    Keywords:   C. elegans ; Alfy; JIP3; LRK-1; LRRK2; UNC-16; WDFY-3; axon; endosomes; neurodevelopment
    DOI:  https://doi.org/10.1093/genetics/iyae053
  29. Cancer Lett. 2024 Apr 05. pii: S0304-3835(24)00249-0. [Epub ahead of print]590 216856
    Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions.
    Qiang Yu, Jiajun Ding, Shisen Li, Yunlong Li.
      Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.
    Keywords:  Apoptosis; Autophagy; Cancer immunotherapy; Immune system; Immune tolerance
    DOI:  https://doi.org/10.1016/j.canlet.2024.216856
  30. Discov Oncol. 2024 Apr 07. 15(1): 107
    Relationship of mTORC1 and ferroptosis in tumors.
    Huilin Liao, Yueqing Wang, Lili Zou, Yanmei Fan, Xinyue Wang, Xiancong Tu, Qiaobai Zhu, Jun Wang, Xiaowen Liu, Chuanjiang Dong.
      Ferroptosis is a novel form of programmed death, dependent on iron ions and oxidative stress, with a predominant intracellular form of lipid peroxidation. In recent years, ferroptosis has gained more and more interest of people in the treatment mechanism of targeted tumors. mTOR, always overexpressed in the tumor, and controlling cell growth and metabolic activities, has an important role in both autophagy and ferroptosis. Interestingly, the selective types of autophay plays an important role in promoting ferroptosis, which is related to mTOR and some metabolic pathways (especially in iron and amino acids). In this paper, we list the main mechanisms linking ferroptosis with mTOR signaling pathway and further summarize the current compounds targeting ferroptosis in these ways. There are growing experimental evidences that targeting mTOR and ferroptosis may have effective impact in many tumors, and understanding the mechanisms linking mTOR to ferroptosis could provide a potential therapeutic approach for tumor treatment.
    Keywords:  AMPK; Autophagy; Ferroptosis; GPX4; Tumors; mTOR
    DOI:  https://doi.org/10.1007/s12672-024-00954-w
  31. Biol Direct. 2024 Apr 06. 19(1): 26
    Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity.
    Mario Villa-González, Marina Rubio, Gerardo Martín-López, Paula R Mallavibarrena, Laura Vallés-Saiz, Denis Vivien, Francisco Wandosell, Maria José Pérez-Álvarez.
      Ischemic stroke is a sudden and acute disease characterized by neuronal death, increment of reactive gliosis (reactive microglia and astrocytes), and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Reactive microglia involve functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such reactive microglial is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia. Here, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury. Our data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.
    Keywords:  Astrocytes; Cerebral ischemia; Glia; MCAO; Microglia; Neuroinflammation; Neurons; Rapamycin; mTORC1
    DOI:  https://doi.org/10.1186/s13062-024-00470-5
  32. Int J Oncol. 2024 Jun;pii: 57. [Epub ahead of print]64(6):
    Beyond self‑eating: Emerging autophagy‑independent functions for the autophagy molecules in cancer (Review).
    Giulia Tedesco, Manuela Santarosa, Roberta Maestro.
      Autophagy is a conserved catabolic process that controls organelle quality, removes misfolded or abnormally aggregated proteins and is part of the defense mechanisms against intracellular pathogens. Autophagy contributes to the suppression of tumor initiation by promoting genome stability, cellular integrity, redox balance and proteostasis. On the other hand, once a tumor is established, autophagy can support cancer cell survival and promote epithelial‑to‑mesenchymal transition. A growing number of molecules involved in autophagy have been identified. In addition to their key canonical activity, several of these molecules, such as ATG5, ATG12 and Beclin‑1, also exert autophagy‑independent functions in a variety of biological processes. The present review aimed to summarize autophagy‑independent functions of molecules of the autophagy machinery and how the activity of these molecules can influence signaling pathways that are deregulated in cancer progression.
    Keywords:  autophagy; autophagy‑independent; cancer; cancer progression; cell death; genome instability; metastasis; proliferation; survival
    DOI:  https://doi.org/10.3892/ijo.2024.5645
  33. Autophagy. 2024 Apr 10.
    Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.
    Yajuan Jiao, Pengwei Zhao, Ling-Dong Xu, Jia-Qi Yu, Hou-Li Cai, Chong Zhang, Chao Tong, Yong-Le Yang, Pinglong Xu, Qiming Sun, Ning Chen, Bin Wang, Yao-Wei Huang.
      Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro. Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo, with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs.
    Keywords:  Coronavirus; PEDV; TBK1; Type I IFN; nsp2; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2340420
  34. Cell Commun Signal. 2024 Apr 09. 22(1): 222
    Csn5 inhibits autophagy by regulating the ubiquitination of Atg6 and Tor to mediate the pathogenicity of Magnaporthe oryzae.
    Zi-Fang Shen, Lin Li, Jing-Yi Wang, Jian Liao, Yun-Ran Zhang, Xue-Ming Zhu, Zi-He Wang, Jian-Ping Lu, Xiao-Hong Liu, Fu-Cheng Lin.
      Csn5 is subunit 5 of the COP9 signalosome (CSN), but the mechanism by which it strictly controls the pathogenicity of pathogenic fungi through autophagy remains unclear. Here, we found that Csn5 deficiency attenuated pathogenicity and enhanced autophagy in Magnaporthe oryzae. MoCSN5 knockout led to overubiquitination and overdegradation of MoTor (the core protein of the TORC1 complex [target of rapamycin]) thereby promoted autophagy. In addition, we identified MoCsn5 as a new interactor of MoAtg6. Atg6 was found to be ubiquitinated through linkage with lysine 48 (K48) in cells, which is necessary for infection-associated autophagy in pathogenic fungi. K48-ubiquitination of Atg6 enhanced its degradation and thereby inhibited autophagic activity. Our experimental results indicated that MoCsn5 promoted K48-ubiquitination of MoAtg6, which reduced the MoAtg6 protein content and thus inhibited autophagy. Aberrant ubiquitination and autophagy in ΔMocsn5 led to pleiotropic defects in the growth, development, stress resistance, and pathogenicity of M. oryzae. In summary, our study revealed a novel mechanism by which Csn5 regulates autophagy and pathogenicity in rice blast fungus through ubiquitination.
    Keywords:  Autophagy; COP9 signalosome; Csn5; Pathogenicity; Rice blast fungus; Ubiquitination
    DOI:  https://doi.org/10.1186/s12964-024-01598-7
  35. Sci Rep. 2024 Apr 11. 14(1): 8451
    Regulation of translation in response to iron deficiency in human cells.
    Mireia S Puig-Segui, Carolyn J Decker, Hanna Barlit, Vyacheslav M Labunskyy, Roy Parker, Sergi Puig.
      Protein synthesis is a highly energy-consuming process that is downregulated in response to many environmental stresses or adverse conditions. Studies in the yeast Saccharomyces cerevisiae have shown that bulk translation is inhibited during adaptation to iron deficiency, which is consistent with its requirement for ribosome biogenesis and recycling. Although iron deficiency anemia is the most common human nutritional disorder, how iron modulates translation in mammals is poorly understood. Studies during erythropoiesis have shown that iron bioavailability is coordinated with globin synthesis via bulk translation regulation. However, little is known about the control of translation during iron limitation in other tissues. Here, we investigated how iron depletion affects protein synthesis in human osteosarcoma U-2 OS cells. By adding an extracellular iron chelator, we observed that iron deficiency limits cell proliferation, induces autophagy, and decreases the global rate of protein synthesis. Analysis of specific molecular markers indicates that the inhibition of bulk translation upon iron limitation occurs through the eukaryotic initiation factor eIF2α and mechanistic target of rapamycin (mTOR) pathways. In contrast to other environmental and nutritional stresses, iron depletion does not trigger the assembly of messenger ribonucleoprotein stress granules, which typically form upon polysome disassembly.
    DOI:  https://doi.org/10.1038/s41598-024-59003-9
  36. Dev Neurosci. 2024 Apr 05.
    TFEB overexpression through GFAP promoter disrupts neuronal lamination by dysregulating neurogenesis during embryonic development.
    Lei Wang, Jiaxin Cao, Haichao Chen, Yuezhang Ma, Yishu Zhang, Xiaomei Su, Yuhong Jing, Yonggang Wang.
       INTRODUCTION: Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, has diverse roles in various physiological processes. Enhancing lysosomal function by TFEB activation has recently been implicated in restoring neural stem cells (NSCs) function. Overexpression of TFEB can inhibit the cell cycle of newborn cortical NSCs. It has also been found that TFEB regulates the pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy lysosomal biogenesis. This study aims to explore the effects of TFEB activation on neurogenesis in vivo through transgenic mice.
    METHODS: We developed a GFAP-driven TFEB overexpression mouse model (TFEB GoE) by crossing the floxed TFEB overexpression mice and hGFAP-cre mice. We performed immunohistochemical and fluorescence staining on brain tissue from newborn mice to assess neurogenesis changes, employing markers such as GFAP, Nestin, Ki67, DCX, Tbr1 and Neun to trace different stages of neural development and cell proliferation.
    RESULTS: TFEB GoE mice exhibited premature mortality, dying at 10-20 days after birth. Immunohistochemical analysis revealed significant abnormalities, including disrupted hippocampal structure and cortical layering. Compared to control mice, TFEB GoE mice showed a marked increase in radial glial cells (RGCs) in the hippocampus and cortex, with Ki67 staining indicating these cells were predominantly in a quiescent state. This suggests that TFEB overexpression suppresses RGCs proliferation. Additionally, abnormal distributions of migrating neurons and mature neurons were observed, highlighted by DCX, Tbr1 and Neun staining, indicating a disruption in normal neurogenesis.
    CONCLUSION: This study, using transgenic animals in vivo, revealed that GFAP-driven TFEB overexpression leads to abnormal neural layering in the hippocampus and cortex by dysregulating neurogenesis. Our study is the first to discover the detrimental impact of TFEB overexpression on neurogenesis during embryonic development, which has important reference significance in future TFEB overexpression interventions in NSCs for treatment.
    DOI:  https://doi.org/10.1159/000538656
  37. Traffic. 2024 Apr;25(4): e12934
    Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing.
    Johanna Mayer, Dominik Boeck, Michelle Werner, Daniela Frankenhauser, Stephan Geley, Hesso Farhan, Makoto Shimozawa, Per Nilsson.
      Alzheimer's disease (AD) pathology is characterized by amyloid beta (Aβ) plaques and dysfunctional autophagy. Aβ is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry-APP-EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry-APP-EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry-APP-EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry-APP-EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry-APP-EGFP transport resulted in increased secreted mCherry-soluble APP and C-terminal fragment-EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD.
    Keywords:  APP; ATG9; Alzheimer; RUSH; autophagy; live cell imaging
    DOI:  https://doi.org/10.1111/tra.12934
  38. Int J Mol Sci. 2024 Mar 28. pii: 3758. [Epub ahead of print]25(7):
    Decoding the Versatile Landscape of Autophagic Protein VMP1 in Cancer: A Comprehensive Review across Tissue Types and Regulatory Mechanisms.
    Felipe J Renna, Claudio D Gonzalez, Maria I Vaccaro.
      Autophagy, a catabolic process orchestrating the degradation of proteins and organelles within lysosomes, is pivotal for maintaining cellular homeostasis. However, its dual role in cancer involves preventing malignant transformation while fostering progression and therapy resistance. Vacuole Membrane Protein 1 (VMP1) is an essential autophagic protein whose expression, per se, triggers autophagy, being present in the whole autophagic flux. In pancreatic cancer, VMP1-whose expression is linked to the Kirsten Rat Sarcoma Virus (KRAS) oncogene-significantly contributes to disease promotion, progression, and chemotherapy resistance. This investigation extends to breast cancer, colon cancer, hepatocellular carcinoma, and more, highlighting VMP1's nuanced nature, contingent on specific tissue contexts. The examination of VMP1's interactions with micro-ribonucleic acids (miRNAs), including miR-21, miR-210, and miR-124, enhances our understanding of its regulatory network in cancer. Additionally, this article discusses VMP1 gene fusions, especially with ribosomal protein S6 kinase B1 (RPS6KB1), shedding light on potential implications for tumor malignancy. By deciphering the molecular mechanisms linking VMP1 to cancer progression, this exploration paves the way for innovative therapeutic strategies to disrupt these pathways and potentially improve treatment outcomes.
    Keywords:  VMP1; autophagy; cancer
    DOI:  https://doi.org/10.3390/ijms25073758
  39. Cancer Lett. 2024 Apr 07. pii: S0304-3835(24)00260-X. [Epub ahead of print] 216867
    Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapetuics.
    Kuan Liu, Huijing Chen, Yanhong Li, Bei Wang, Qian Li, Lu Zhang, Xiaohui Liu, Ce Wang, Yavuz Nuri Ertas, Hongyun Shi.
      Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.
    Keywords:  Autophagy; Bladder cancer; Cell death interactions; Nanoparticles; Non-coding RNAs
    DOI:  https://doi.org/10.1016/j.canlet.2024.216867
  40. Eur J Pharmacol. 2024 Apr 09. pii: S0014-2999(24)00256-5. [Epub ahead of print] 176568
    Novel combinatorial autophagy inhibition therapy for triple negative breast cancers.
    Yomna S Abd El-Aziz, Taymin du Toit-Thompson, Matthew J McKay, Mark P Molloy, Shihani Stoner, Betty McDowell, Elizabeth Moon, Loretta Sioson, Amy Sheen, Angela Chou, Anthony J Gill, Patric J Jansson, Sumit Sahni.
       BACKGROUND: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes. It is characterized by lack of estrogen, progesterone and human epidermal growth factor 2 receptors, and thus, have limited therapeutic options. Autophagy has been found to be correlated with poor prognosis and aggressive behaviour in TNBC. This study aimed to target autophagy in TNBC via a novel approach to inhibit TNBC progression.
    METHODS: Immunoblotting and confocal microscopy were carried out to examine the effect of tumor microenvironmental stressors on autophagy. Cellular proliferation and migration assays were used to test the effect of different autophagy inhibitors and standard chemotherapy alone or in combination. In vivo xenograft mouse model was utilized to assess the effect of autophagy inhibitors alone or in combination with Paclitaxel. High resolution mass spectrometry based proteomic analysis was performed to explore the mechanisms behind chemoresistance in TNBC. Lastly, immunohistochemistry was done to assess the correlation between autophagic related proteins and clinical characteristics in TNBC tissue specimens.
    RESULTS: Metabolic stressors were found to induce autophagy in TNBC cell lines. Autophagy initiation inhibitors, SAR405 and MRT68921, showed marked synergy in their anti-proliferative activity in both chemosensitive and chemoresistant TNBC cell models. Paradoxically, positive expression of autophagosome marker LC3 was shown to be associated with better overall survival of TNBC patients.
    CONCLUSION: In this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of novel treatment modality against TNBC.
    Keywords:  Autophagy; Autophagy inhibitors; Chemoresistance; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176568
  41. Front Cell Infect Microbiol. 2024 ;14 1268243
    Identification of autophagy receptors for the Crohn's disease-associated adherent-invasive Escherichia coli.
    Alison Da Silva, Guillaume Dalmasso, Anaïs Larabi, My Hanh Thi Hoang, Elisabeth Billard, Nicolas Barnich, Hang Thi Thu Nguyen.
       Introduction: Crohn's disease (CD) is a chronic inflammatory bowel disease, of which the etiology involves genetic, environmental and microbial factors. Adherent-invasive Escherichia coli (AIEC) and polymorphisms in autophagy-related genes have been implicated in CD etiology. Autophagy is a key process for the maintenance of cellular homeostasis, which allows the degradation of damaged cytoplasmic components and pathogens via lysosome. We have shown that a functional autophagy is necessary for AIEC clearance. Here, we aimed at identifying the autophagy receptor(s) responsible to target AIEC to autophagy for degradation.
    Methods: The levels of autophagy receptors p62, NDP52, NBR1, TAX1BP1 and Optineurin were knocked down in human intestinal epithelial cells T84 using siRNAs. The NDP52 knock-out (KO) and p62 KO HeLa cells, as well as NDP52 KO HeLa cells expressing the wild-type NDP52 or the mutated NDP52Val248Ala protein were used.
    Results and discussion: We showed that, among the tested autophagy receptors (p62, NDP52, NBR1, TAX1BP1 and Optineurin), diminished expression of p62 or NDP52 increased the number of the clinical AIEC LF82 strain inside epithelial cells. This was associated with increased pro-inflammatory cytokine production. Moreover, p62 or NDP52 directly colocalized with AIEC LF82 and LC3, an autophagy marker. As the NDP52Val248Ala polymorphism has been associated with increased CD susceptibility, we investigated its impact on AIEC control. However, in HeLa cell and under our experimental condition, no effect of this polymorphism neither on AIEC LF82 intracellular number nor on pro-inflammatory cytokine production was observed. Together, our results suggest that p62 and NDP52 act as autophagy receptors for AIEC recognition, controlling AIEC intracellular replication and inflammation.
    Keywords:  Crohn’s disease; NDP52; adherent-invasive E. coli (AIEC); autophagy; p62
    DOI:  https://doi.org/10.3389/fcimb.2024.1268243
  42. Aging Dis. 2024 Mar 25.
    Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population.
    Mingwei Wang, Xiangzhi Wu, Yuyao Jiao, Wenli Yin, Lili Zhang.
      Numerous bodily processes deteriorate with age, chief among them being the loss of muscle mass and function. The condition referred to as aging myasthenia gravis impairs older persons' quality of life and is linked to a higher risk of several chronic illnesses. An increasing number of studies conducted in the last several years has demonstrated that moderate exercise can halt this process. Specifically, by promoting autophagy, aerobic exercise helps to postpone the onset of senile myasthenia gravis. In this work, we will explore how aerobic exercise modulates autophagy to prevent muscle aging and examine the most recent findings in this area of study. We discovered that exercise-induced autophagy can effectively balance protein degradation and relieve skeletal muscle atrophy by looking through pertinent literature. Aerobic exercise has a direct impact on autophagy, but it can also delay the onset of senile myasthenia gravis by enhancing blood flow, lowering inflammation, and boosting muscle oxidative capacity. In order to postpone the onset of senile myasthenia gravis, research on the mechanism of action of aerobic exercise in inducing autophagy will be discussed in detail in this study.
    DOI:  https://doi.org/10.14336/AD.2024.0318
  43. Basic Clin Pharmacol Toxicol. 2024 Apr 07.
    Optimizing myocardial cell protection with xanthine derivative KMUP-3 potentiates autophagy through the PI3K/Akt/eNOS axis.
    Shang-En Huang, Jong-Hau Hsu, Bo-Wen Shiau, Yi-Ching Liu, Bin-Nan Wu, Zen-Kong Dai, Chung-Pin Liu, Jwu-Lai Yeh.
       BACKGROUND: Autophagy can have either beneficial or detrimental effects on various heart diseases. Pharmacological interventions improve cardiac function, which is correlated with enhanced autophagy. To assess whether a xanthine derivative (KMUP-3) treatment coincides with enhanced autophagy while also providing cardio-protection, we investigated the hypothesis that KMUP-3 treatment activation of autophagy through PI3K/Akt/eNOS signalling offered cardioprotective properties.
    METHODS: The pro-autophagic effect of KMUP-3 was performed in a neonatal rat model targeting cardiac fibroblasts and cardiomyocytes, and by assessing the impact of KMUP-3 treatment on cardiotoxicity, we used antimycin A-induced cardiomyocytes.
    RESULTS: As determined by transmission electron microscopy observation, KMUP-3 enhanced autophagosome formation in cardiac fibroblasts. Furthermore, KMUP-3 significantly increased the expressions of autophagy-related proteins, LC3 and Beclin-1, both in a time- and dose-dependent manner; moreover, the pro-autophagy and nitric oxide enhancement effects of KMUP-3 were abolished by inhibitors targeting eNOS and PI3K in cardiac fibroblasts and cardiomyocytes. Notably, KMUP-3 ameliorated cytotoxic effects induced by antimycin A, demonstrating its protective autophagic response.
    CONCLUSION: These findings enable the core pathway of PI3K/Akt/eNOS axis in KMUP-3-enhanced autophagy activation and suggest its principal role in safeguarding against cardiotoxicity.
    Keywords:  autophagy; cardio‐protection; endothelial nitric oxide synthase; nitric oxide; xanthine derivative KMUP‐3
    DOI:  https://doi.org/10.1111/bcpt.14007
  44. World J Mens Health. 2024 Apr 08.
    The Role of Autophagy in Erectile Dysfunction.
    Changjing Wu, Yang Xiong, Fudong Fu, Fuxun Zhang, Feng Qin, Jiuhong Yuan.
      Autophagy is a conservative lysosome-dependent material catabolic pathway, and exists in all eukaryotic cells. Autophagy controls cell quality and survival by eliminating intracellular dysfunction substances, and plays an important role in various pathophysiology processes. Erectile dysfunction (ED) is a common male disease. It is resulted from a variety of causes and pathologies, such as diabetes, hypertension, hyperlipidemia, aging, spinal cord injury, or cavernous nerve injury caused by radical prostatectomy, and others. In the past decade, autophagy has begun to be investigated in ED. Subsequently, an increasing number of studies have revealed the regulation of autophagy contributes to the recovery of ED, and which is mainly involved in improving endothelial function, smooth muscle cell apoptosis, penile fibrosis, and corpus cavernosum nerve injury. Therefore, in this review, we aim to summarize the possible role of autophagy in ED from a cellular perspective, and we look forward to providing a new idea for the pathogenesis investigation and clinical treatment of ED in the future.
    Keywords:  Apoptosis; Autophagy; Endothelial cells; Erectile dysfunction; Fibrosis; Smooth muscle
    DOI:  https://doi.org/10.5534/wjmh.230145
  45. Mol Biol Cell. 2024 Apr 10. mbcE24010025
    WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.
    Alyssa M Coulter, Valerie Cortés, Corey J Theodore, Rachel E Cianciolo, Ron Korstanje, Kenneth G Campellone.
      The actin cytoskeleton is essential for many functions of eukaryotic cells, but the factors that nucleate actin assembly are not well understood at the organismal level or in the context of disease. To explore the function of the actin nucleation factor WHAMM in mice, we examined how Whamm inactivation impacts kidney physiology and cellular proteostasis. We show that male WHAMM knockout mice excrete elevated levels of albumin, glucose, phosphate, and amino acids, and display structural abnormalities of the kidney proximal tubule, suggesting that WHAMM activity is important for nutrient reabsorption. In kidney tissue, the loss of WHAMM results in the accumulation of the lipidated autophagosomal membrane protein LC3, indicating an alteration in autophagy. In mouse fibroblasts and human proximal tubule cells, WHAMM and its binding partner the Arp2/3 complex control autophagic membrane closure and cargo receptor recruitment. These results reveal a role for WHAMM-mediated actin assembly in maintaining kidney function and promoting proper autophagosome membrane remodeling.
    DOI:  https://doi.org/10.1091/mbc.E24-01-0025
  46. Exp Gerontol. 2024 Apr 11. pii: S0531-5565(24)00070-6. [Epub ahead of print]190 112428
    PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
    Yimin Fu, Lei Tao, Xiaojun Wang, Binyou Wang, Weilin Qin, Lei Song.
       BACKGROUND: Mitochondrial dysregulation in skeletal myocytes is considered a major factor in aged sarcopenia. In this study, we aimed to study the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on Sestrin2-mediated mechanistic target of rapamycin complex 1 (mTORC1) in aged skeletal muscles.
    METHODS: C2C12 myoblasts were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of DNA damage, mitochondrial membrane potential (Δψm), mitochondrial ROS and PGC-1α protein. The PGC-1α silence in the C2C12 cells was established by siRNA transfection. The levels of DNA damage, Δψm, mitochondrial ROS, Sestrin2 and p-S6K1/S6K1 proteins were observed after the PGC-1α silence in the C2C12 cells. Recombinant Sestrin2 treatment was used to observe the changes of DNA damage, Δψm, mitochondrial ROS and p-S6K1/S6K1 protein in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. Wild-type (WT) mice and muscle-specific PGC-1α conditional knockout (MKO) mice, including young and old, were used to analyse the effects of PGC-1α on muscle function and the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles. Recombinant Sestrin2 was administrated to analyse its effects on muscle function in the old WT mice and old MKO mice.
    RESULTS: 7β-OHC treatment induced DNA damage, mitochondrial dysfunction and decrease of PGC-1α protein in the C2C12 cells. PGC-1α silence also induced DNA damage and mitochondrial dysfunction in the C2C12 cells. Additionally, PGC-1α silence or 7β-OHC treatment decreased the levels of Sestrin2 and p-S6K1/S6K1 protein in the C2C12 cells. Recombinant Sestrin2 treatment significantly improved the DNA damage and mitochondrial dysfunction in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia and decreased the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles when compared to the WT mice. Recombinant Sestrin2 treatment improved muscle function and increased p-S6K1 levels in the old two genotypes.
    CONCLUSION: This research demonstrates that PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.
    Keywords:  7β-hydroxycholesterol; Mitochondrial dysregulation; Muscle function; PGC-1α conditional knockout
    DOI:  https://doi.org/10.1016/j.exger.2024.112428
  47. Front Cell Dev Biol. 2024 ;12 1360014
    Role of autophagy in ischemic stroke: insights from animal models and preliminary evidence in the human disease.
    Rosita Stanzione, Donatella Pietrangelo, Maria Cotugno, Maurizio Forte, Speranza Rubattu.
      Stroke represents a main cause of death and permanent disability worldwide. The molecular mechanisms underlying cerebral injury in response to the ischemic insults are not completely understood. In this article, we summarize recent evidence regarding the role of autophagy in the pathogenesis of ischemic stroke by reviewing data obtained in murine models of either transient or permanent middle cerebral artery occlusion, and in the stroke-prone spontaneously hypertensive rat. Few preliminary observational studies investigating the role of autophagy in subjects at high cerebrovascular risk and in cohorts of stroke patients were also reviewed. Autophagy plays a dual role in neuronal and vascular cells by exerting both protective and detrimental effects depending on its level, duration of stress and type of cells involved. Protective autophagy exerts adaptive mechanisms which reduce neuronal loss and promote survival. On the other hand, excessive activation of autophagy leads to neuronal cell death and increases brain injury. In conclusion, the evidence reviewed suggests that a proper manipulation of autophagy may represent an interesting strategy to either prevent or reduce brain ischemic injury.
    Keywords:  animal models; autophagy; human disease; ischemic stroke; mTOR; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2024.1360014
  48. J Neurosci. 2024 Apr 08. pii: e1256232024. [Epub ahead of print]
    Impairment of the glial phagolysosomal system drives prion-like propagation in a Drosophila model of Huntington's disease.
    Graham H Davis, Aprem Zaya, Margaret M Panning Pearce.
      Protein misfolding, aggregation, and spread through the brain are primary drivers of neurodegenerative diseases pathogenesis. Phagocytic glia are responsible for regulating the load of pathogenic protein aggregates in the brain, but emerging evidence suggests that glia may also act as vectors for aggregate spread. Accumulation of protein aggregates could compromise the ability of glia to eliminate toxic materials from the brain by disrupting efficient degradation in the phagolysosomal system. A better understanding of phagocytic glial cell deficiencies in the disease state could help to identify novel therapeutic targets for multiple neurological disorders. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade neuronal debris in male and female adult Drosophila expressing the gene that causes Huntington's disease (HD). mHTT aggregate formation in neurons impairs engulfment and clearance of injured axons and causes accumulation of phagolysosomes in glia. Neuronal mHTT expression induces upregulation of key innate immunity and phagocytic genes, some of which were found to regulate mHTT aggregate burden in the brain. Finally, a forward genetic screen revealed Rab10 as a novel component of Draper-dependent phagocytosis that regulates mHTT aggregate transmission from neurons to glia. These data suggest that glial phagocytic defects enable engulfed mHTT aggregates to evade lysosomal degradation and acquire prion-like characteristics. Together, our findings reveal new mechanisms that enhance our understanding of the beneficial and potentially harmful effects of phagocytic glia in HD and potentially other neurodegenerative diseases.Significance Statement Deposition of amyloid aggregates is strongly associated with neurodegenerative disease progression and neuronal cell loss. Many studies point to glial cells as dynamic mediators of disease, capable of phagocytosing toxic materials, but also promoting chronic inflammation and proteopathic aggregate spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in a Drosophila model of Huntington's disease that neuronal mHTT aggregates interfere with glial phagocytic engulfment, phagolysosomal processing, and innate immunity transcriptional responses. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates. Our findings add to a growing narrative of glia as double-edged players in neurodegenerative diseases.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1256-23.2024
  49. Eur J Cell Biol. 2024 Apr 05. pii: S0171-9335(24)00028-1. [Epub ahead of print]103(2): 151411
    Degradation of hexosylceramides is required for timely corpse clearance via formation of cargo-containing phagolysosomal vesicles.
    Rebecca Holzapfel, Agata Prell, Fabian Schumacher, Veronika Perschin, José Pedro Friedmann Angeli, Burkhard Kleuser, Christian Stigloher, Gholamreza Fazeli.
      Efficient degradation of phagocytic cargo in lysosomes is crucial to maintain cellular homeostasis and defending cells against pathogens. However, the mechanisms underlying the degradation and recycling of macromolecular cargo within the phagolysosome remain incompletely understood. We previously reported that the phagolysosome containing the corpse of the polar body in C. elegans tubulates into small vesicles to facilitate corpse clearance, a process that requires cargo protein degradation and amino acid export. Here we show that degradation of hexosylceramides by the prosaposin ortholog SPP-10 and glucosylceramidases is required for timely corpse clearance. We observed accumulation of membranous structures inside endolysosomes of spp-10-deficient worms, which are likely caused by increased hexosylceramide species. spp-10 deficiency also caused alteration of additional sphingolipid subclasses, like dihydroceramides, 2-OH-ceramides, and dihydrosphingomyelins. While corpse engulfment, initial breakdown of corpse membrane inside the phagolysosome and lumen acidification proceeded normally in spp-10-deficient worms, formation of the cargo-containing vesicles from the corpse phagolysosome was reduced, resulting in delayed cargo degradation and phagolysosome resolution. Thus, by combining ultrastructural studies and sphingolipidomic analysis with observing single phagolysosomes over time, we identified a role of prosaposin/SPP-10 in maintaining phagolysosomal structure, which promotes efficient resolution of phagocytic cargos.
    Keywords:  Cell corpse clearance; Glucosyl ceramidases; Hexosylceramides; Lysosome; Phagolysosome resolution; Polar body; Sphingolipidome
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151411
  50. Am J Physiol Cell Physiol. 2024 Apr 08.
    Metformin Mitigates Adipogenesis of Fibro-adipogenic Progenitors After Rotator Cuff Tears Via Activating mTOR/ULK1 Mediated Autophagy.
    Hao Zhou, Xingzuan Lin, Shujing Feng, Siyuan Zhu, Han Zhou, Huifang Chen, He Youwu, Zekai Wang, Ru Wang, Xiexiang Shao, Jianhua Wang.
      Muscular fatty infiltration is a common issue after rotator cuff tears (RCT) which impairs shoulder function. Females suffer higher prevalence and more severe degree of muscular fatty infiltration after RCT when compared to males, with the underlying mechanisms remaining unclear. Fibro/adipogenic progenitors (FAPs) are the primary source of muscular fatty infiltration following RCT. Our findings disclose that gender-specific disparities in muscular fatty infiltration are linked to mTOR/ULK1-mediated autophagy of FAPs. Decreased autophagic activity contributes to adipogenic differentiation in female FAPs after RCT. Furthermore, metformin could enhance mTOR/ULK1 mediated autophagic processes of FAPs, thereby alleviating fatty infiltration and improving shoulder functionality after RCT. Together, our study reveals that gender differences in muscular fatty infiltration arise from distinct autophagic activities. Metformin could be a promising non-invasive intervention to ameliorate muscular fatty infiltration of RCT.
    Keywords:  Autophagy; Muscular fatty infiltration; Rotator cuff tear; fibro-adipogenic progenitors; mTOR/ULK1 signaling pathway
    DOI:  https://doi.org/10.1152/ajpcell.00034.2024
  51. iScience. 2024 Apr 19. 27(4): 109580
    Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy.
    Clotilde C N Renaud, Carolina Alves Nicolau, Clément Maghe, Kilian Trillet, Jane Jardine, Sophie Escot, Nicolas David, Julie Gavard, Nicolas Bidère.
      Centriolar satellites are high-order assemblies, scaffolded by the protein PCM1, that gravitate as particles around the centrosome and play pivotal roles in fundamental cellular processes notably ciliogenesis and autophagy. Despite stringent control mechanisms involving phosphorylation and ubiquitination, the landscape of post-translational modifications shaping these structures remains elusive. Here, we report that necrosulfonamide (NSA), a small molecule known for binding and inactivating the pivotal effector of cell death by necroptosis MLKL, intersects with centriolar satellites, ciliogenesis, and autophagy independently of MLKL. NSA functions as a potent redox cycler and triggers the oxidation and aggregation of PCM1 alongside select partners, while minimally impacting the overall distribution of centriolar satellites. Additionally, NSA-mediated ROS production disrupts ciliogenesis and leads to the accumulation of autophagy markers, partially alleviated by PCM1 deletion. Together, these results identify PCM1 as a redox sensor protein and provide new insights into the interplay between centriolar satellites and autophagy.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.109580
  52. Cell Mol Life Sci. 2024 Apr 10. 81(1): 171
    The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation.
    Max Zachrisson Totland, Lars Mørland Knudsen, Nikoline Lander Rasmussen, Yasufumi Omori, Vigdis Sørensen, Vilde C Wivestad Elster, Jakob Mørkved Stenersen, Mathias Larsen, Caroline Lunder Jensen, Anna A Zickfeldt Lade, Emilie Bruusgaard, Sebastian Basing, Kushtrim Kryeziu, Andreas Brech, Trond Aasen, Ragnhild A Lothe, Edward Leithe.
      Intercellular communication via gap junctions has a fundamental role in regulating cell growth and tissue homeostasis, and its dysregulation may be involved in cancer development and radio- and chemotherapy resistance. Connexin43 (Cx43) is the most ubiquitously expressed gap junction channel protein in human tissues. Emerging evidence indicates that dysregulation of the sorting of Cx43 to lysosomes is important in mediating the loss of Cx43-based gap junctions in cancer cells. However, the molecular basis underlying this process is currently poorly understood. Here, we identified the E3 ubiquitin ligase ITCH as a novel regulator of intercellular communication via gap junctions. We demonstrate that ITCH promotes loss of gap junctions in cervical cancer cells, which is associated with increased degradation of Cx43 in lysosomes. The data further indicate that ITCH interacts with and regulates Cx43 ubiquitination and that the ITCH-induced loss of Cx43-based gap junctions requires its catalytic HECT (homologous to E6-AP C-terminus) domain. The data also suggest that the ability of ITCH to efficiently promote loss of Cx43-based gap junctions and degradation of Cx43 depends on a functional PY (PPXY) motif in the C-terminal tail of Cx43. Together, these data provide new insights into the molecular basis underlying the degradation of Cx43 and have implications for the understanding of how intercellular communication via gap junctions is lost during cancer development.
    Keywords:  Cervix; Connexin; Deubiquitination; Endosome; NEDD4
    DOI:  https://doi.org/10.1007/s00018-024-05165-8
  53. Environ Pollut. 2024 Apr 09. pii: S0269-7491(24)00586-4. [Epub ahead of print] 123872
    6PPDQ induces cardiomyocyte senescence via AhR/ROS-mediated autophagic flux blockage.
    Baoqiang Fu, Tao Chen, Bin Jiang, Haobin Feng, Ziyu Zhu, Min Li, Guoxing Zhang, Yan Jiang.
      Recently, attention has been drawn to the adverse outcomes of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ) on human health, but its cardiac toxicity has been relatively understudied. This work aims to investigate the effects of 6PPDQ on differentiated H9c2 cardiomyocytes. Our findings demonstrated that exposure to 6PPDQ altered cellular morphology and disrupted the expression of cardiac-specific markers. Significantly, 6PPDQ exposure led to cardiomyocyte senescence, characterized by elevated β-Galactosidase activity, upregulation of cell cycle inhibitor, induction of DNA double-strand breaks, and remodeling of Lamin B1. Furthermore, 6PPDQ hindered autophagy flux by promoting the formation of autophagosomes while inhibiting the degradation of autolysosomes. Remarkably, restoration of autophagic flux using rapamycin counteracted 6PPDQ-induced cardiomyocyte senescence. Additionally, our study revealed that 6PPDQ significantly increased the ROS production. However, ROS scavenger effectively reduced the blockage of autophagic flux and cardiomyocyte senescence caused by 6PPDQ. Furthermore, we discovered that 6PPDQ activated the Aryl hydrocarbon receptor (AhR) signaling pathway. AhR antagonist was found to reverse the blockage of autophagy and alleviate cardiac senescence, while also reducing ROS levels in 6PPDQ-treated group. In conclusion, our research unveils that exposure to 6PPDQ induces ROS overproduction through AhR activation, leading to disruption of autophagy flux and ultimately contributing to cardiomyocyte senescence.
    Keywords:  6PPDQ; AhR; Autophagy; Cardiomyocytes; Oxidative stress; Senescence
    DOI:  https://doi.org/10.1016/j.envpol.2024.123872
  54. Cancer Lett. 2024 Apr 05. pii: S0304-3835(24)00253-2. [Epub ahead of print] 216860
    Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.
    Gang Zhao, Yutao Wang, Zhongru Fan, Jian Xiong, Yavuz Nuri Ertas, Nureddin Ashammakhi, Jianfeng Wang, Ting Ma.
      Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.
    Keywords:  Apoptosis; Autophagy; Cancer therapy; Cell death; Nanoparticles
    DOI:  https://doi.org/10.1016/j.canlet.2024.216860
  55. Autophagy. 2024 Apr 09. 1-22
    Alcohol-induced Golgiphagy is triggered by the downregulation of Golgi GTPase RAB3D.
    Amanda J Macke, Taylor E Divita, Artem N Pachikov, Sundararajan Mahalingam, Ramesh Bellamkonda, Karuna Rasineni, Carol A Casey, Armen Petrosyan.
      The development of alcohol-associated liver disease (ALD) is associated with disorganized Golgi apparatus and accelerated phagophore formation. While Golgi membranes may contribute to phagophores, association between Golgi alterations and macroautophagy/autophagy remains unclear. GOLGA4/p230 (golgin A4), a dimeric Golgi matrix protein, participates in phagophore formation, but the underlying mechanism is elusive. Our prior research identified ethanol (EtOH)-induced Golgi scattering, disrupting intra-Golgi trafficking and depleting RAB3D GTPase from the trans-Golgi. Employing various techniques, we analyzed diverse cellular and animal models representing chronic and chronic/binge alcohol consumption. In trans-Golgi of non-treated hepatocytes, we found a triple complex formed between RAB3D, GOLGA4, and MYH10/NMIIB (myosin, heavy polypeptide 10, non-muscle). However, EtOH-induced RAB3D downregulation led to MYH10 segregation from the Golgi, accompanied by Golgi fragmentation and tethering of the MYH10 isoform, MYH9/NMIIA, to dispersed Golgi membranes. EtOH-activated autophagic flux is evident through increased WIPI2 recruitment to the Golgi, phagophore formation, enhanced LC3B lipidation, and reduced SQSTM1/p62. Although GOLGA4 dimerization and intra-Golgi localization are unaffected, loss of RAB3D leads to an extension of the cytoplasmic N terminal domain of GOLGA4, forming GOLGA4-positive phagophores. Autophagy inhibition by hydroxychloroquine (HCQ) prevents alcohol-mediated Golgi disorganization, restores distribution of ASGR (asialoglycoprotein receptor), and mitigates COL (collagen) deposition and steatosis. In contrast to short-term exposure to HCQ, extended co-treatment with both EtOH and HCQ results in the depletion of LC3B protein via proteasomal degradation. Thus, (a) RAB3D deficiency and GOLGA4 conformational changes are pivotal in MYH9-driven, EtOH-mediated Golgiphagy, and (b) HCQ treatment holds promise as a therapeutic approach for alcohol-induced liver injury.Abbreviation: ACTB: actin, beta; ALD: alcohol-associated liver disease; ASGR: asialoglycoprotein receptor; AV: autophagic vacuoles; EM: electron microscopy; ER: endoplasmic reticulum; EtOH: ethanol; HCQ: hydroxychloroquine; IP: immunoprecipitation; KD: knockdown; KO: knockout; MYH10/NMIIB: myosin, heavy polypeptide 10, non-muscle; MYH9/NMIIA: myosin, heavy polypeptide 9, non-muscle; PLA: proximity ligation assay; ORO: Oil Red O staining; PM: plasma membrane; TGN: trans-Golgi network; SIM: structured illumination super-resolution microscopy.
    Keywords:  Alcohol; GOLGA4; Golgi disorganization; RAB3D GTPase; autophagy; liver damage
    DOI:  https://doi.org/10.1080/15548627.2024.2329476
  56. Nat Neurosci. 2024 Apr 10.
    Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration.
    Raffaella De Pace, Saikat Ghosh, Veronica H Ryan, Mira Sohn, Michal Jarnik, Paniz Rezvan Sangsari, Nicole Y Morgan, Ryan K Dale, Michael E Ward, Juan S Bonifacino.
      In neurons, RNA granules are transported along the axon for local translation away from the soma. Recent studies indicate that some of this transport involves hitchhiking of RNA granules on lysosome-related vesicles. In the present study, we leveraged the ability to prevent transport of these vesicles into the axon by knockout of the lysosome-kinesin adaptor BLOC-one-related complex (BORC) to identify a subset of axonal mRNAs that depend on lysosome-related vesicles for transport. We found that BORC knockout causes depletion of a large group of axonal mRNAs mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This depletion results in mitochondrial defects and eventually leads to axonal degeneration in human induced pluripotent stem cell (iPSC)-derived and mouse neurons. Pathway analyses of the depleted mRNAs revealed a mechanistic connection of BORC deficiency with common neurodegenerative disorders. These results demonstrate that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration.
    DOI:  https://doi.org/10.1038/s41593-024-01619-1
  57. Acta Neuropathol. 2024 Apr 07. 147(1): 69
    Regulated cell death and its role in Alzheimer's disease and amyotrophic lateral sclerosis.
    Dietmar Rudolf Thal, Klara Gawor, Sebastiaan Moonen.
      Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.
    DOI:  https://doi.org/10.1007/s00401-024-02722-0
  58. Cell Commun Signal. 2024 Apr 09. 22(1): 223
    Atg5 deficiency in macrophages protects against kidney fibrosis via the CCR6-CCL20 axis.
    Yufeng Zhu, Jiexing Tan, Yuanzhan Wang, Yuhong Gong, Xiaoyong Zhang, Ziguo Yuan, Xinyu Lu, Huifang Tang, Zhiming Zhang, Xiaotao Jiang, Wei Zhu, Li Gong.
       BACKGROUND: Autophagy is a lysosome-dependent degradation pathway that regulates macrophage activation, differentiation, and polarization. Autophagy related 5 (Atg5) is a key protein involved in phagocytic membrane elongation in autophagic vesicles that forms a complex with Atg12 and Atg16L1. Alterations in Atg5 are related to both acute and chronic kidney diseases in experimental models. However, the role of macrophage-expressed Atg5 in acute kidney injury remains unclear.
    METHODS: Using a myeloid cell-specific Atg5 knockout (MΦ atg5-/-) mouse, we established renal ischemia/reperfusion and unilateral ureteral obstruction models to evaluate the role of macrophage Atg5 in renal macrophage migration and fibrosis.
    RESULTS: Based on changes in the serum urea nitrogen and creatinine levels, Atg5 deletion had a minimal effect on renal function in the early stages after mild injury; however, MΦ atg5-/- mice had reduced renal fibrosis and reduced macrophage recruitment after 4 weeks of ischemia/reperfusion injury and 2 weeks of unilateral ureteral obstruction injury. Atg5 deficiency impaired the CCL20-CCR6 axis after severe ischemic kidneys. Chemotactic responses of bone marrow-derived monocytes (BMDMs) from MΦ atg5-/- mice to CCL20 were significantly attenuated compared with those of wild-type BMDMs, and this might be caused by the inhibition of PI3K, AKT, and ERK1/2 activation.
    CONCLUSIONS: Our data indicate that Atg5 deficiency decreased macrophage migration by impairing the CCL20-CCR6 axis and inhibited M2 polarization, thereby improving kidney fibrosis.
    Keywords:  Acute kidney injury; Autophagy; Autophagy-related 5; Macrophage; Renal fibrosis
    DOI:  https://doi.org/10.1186/s12964-024-01600-2
  59. Anal Chem. 2024 Apr 10.
    Versatile Fluorescence Lifetime-Based Copper Probe to Quantify Mitochondrial Membrane Potential and Reveal Its Interaction with Protein Aggregation.
    Yu Xiao, Jingyang Wan, Xiaochen Gao, Yu Wei, Jiabao Fang, Baoxing Shen.
      Mitochondria play a crucial role in maintaining cellular homeostasis, and the depolarization of mitochondrial membrane potential (MMP) is an important signal of apoptosis. Additionally, protein misfolding and aggregation are closely related to diseases including neurodegenerative diseases, diabetes, and cancers. However, the interaction between MMP changes and disease-related protein aggregation was rarely studied. Herein, we report a novel "turn-on" fluorescent probe MitoRhB that specifically targets to mitochondria for Cu2+ detection in situ. The fluorescence lifetime (τ) of MitoRhB exhibits a positive correlation with MMP changes, allowing us to quantitatively determine the relative MMP during SOD1 (A4 V) protein aggregation. Finally, we found that (1) the increasing concentrations of copper will accelerate the depolarization of mitochondria and reduce MMP; (2) the depolarization of mitochondria can intensify the degree of protein aggregation, suggesting a new routine of copper-induced cell death mediated through abnormal MMP depolarization and protein aggregation.
    DOI:  https://doi.org/10.1021/acs.analchem.4c00909
  60. bioRxiv. 2024 Mar 27. pii: 2024.03.26.586828. [Epub ahead of print]
    Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2.
    Felix Kraus, Yuchen He, Sharan Swarup, Katherine A Overmyer, Yizhi Jiang, Johann Brenner, Cristina Capitanio, Anna Bieber, Annie Jen, Nicole M Nightingale, Benton J Anderson, Chan Lee, Joao A Paulo, Ian R Smith, Jürgen M Plitzko, Brenda A Schulman, Florian Wilfling, Joshua J Coon, J Wade Harper.
      Lysosomal storage diseases (LSDs) comprised ∼50 monogenic diseases characterized by the accumulation of cellular material in lysosomes and associated defects in lysosomal function, but systematic molecular phenotyping is lacking. Here, we develop a nanoflow-based multi-omic single-shot technology (nMOST) workflow allowing simultaneously quantify HeLa cell proteomes and lipidomes from more than two dozen LSD mutants, revealing diverse molecular phenotypes. Defects in delivery of ferritin and its autophagic receptor NCOA4 to lysosomes (ferritinophagy) were pronounced in NPC2 -/- cells, which correlated with increased lyso-phosphatidylcholine species and multi-lamellar membrane structures visualized by cryo-electron-tomography. Ferritinophagy defects correlated with loss of mitochondrial cristae, MICOS-complex components, and electron transport chain complexes rich in iron-sulfur cluster proteins. Strikingly, mitochondrial defects were alleviated when iron was provided through the transferrin system. This resource reveals how defects in lysosomal function can impact mitochondrial homeostasis in trans and highlights nMOST as a discovery tool for illuminating molecular phenotypes across LSDs.
    DOI:  https://doi.org/10.1101/2024.03.26.586828
  61. J Biol Chem. 2024 Apr 08. pii: S0021-9258(24)01771-X. [Epub ahead of print] 107270
    TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
    Suli Lv, Zongbiao Zhang, Zhenyong Li, Qian Ke, Xianyun Ma, Neng Li, Xuefeng Zhao, Qingli Zou, Lidong Sun, Tanjing Song.
      Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An ,intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. Whether and how TFE3 responds to glucose starvation remain unclear. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.
    Keywords:  O-GlcNAcylation; amino acid transporter; kidney cancer; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2024.107270
  62. Front Cell Dev Biol. 2024 ;12 1370012
    Activating transcription factor 4: a regulator of stress response in human cancers.
    Di Wu, Jie Liang.
      Activating transcription factor 4 (ATF4) is an adaptive response regulator of metabolic and oxidative homeostasis. In response to cellular stress, ATF4 is activated and functions as a regulator to promote cell adaptation for survival. As a transcriptional regulator, ATF4 also widely participates in the regulation of amino acid metabolism, autophagy, redox homeostasis and endoplasmic reticulum stress. Moreover, ATF4 is associated with the initiation and progression of glioblastoma, hepatocellular carcinoma, colorectal cancer, gastric cancer, breast cancer, prostate cancer and lung cancer. This review primarily aims to elucidate the functions of ATF4 and its role in multiple cancer contexts. This review proposes potential therapeutic targets for clinical intervention.
    Keywords:  autophagy; cancer; metabolism; stress; transcription
    DOI:  https://doi.org/10.3389/fcell.2024.1370012
  63. Heliyon. 2024 Apr 15. 10(7): e28959
    Crosstalk between autophagy and ferroptosis mediate injury in ischemic stroke by generating reactive oxygen species.
    Xing-Yu Zhang, Ping-Ping Han, Yi-Ning Zhao, Xin-Ya Shen, Xia Bi.
      Stroke represents a significant threat to global human health, characterized by high rates of morbidity, disability, and mortality. Predominantly, strokes are ischemic in nature. Ischemic stroke (IS) is influenced by various cell death pathways, notably autophagy and ferroptosis. Recent studies have increasingly highlighted the interplay between autophagy and ferroptosis, a process likely driven by the accumulation of reactive oxygen species (ROS). Post-IS, either the inhibition of autophagy or its excessive activation can escalate ROS levels. Concurrently, the interaction between ROS and lipids during ferroptosis further augments ROS accumulation. Elevated ROS levels can provoke endoplasmic reticulum stress-induced autophagy and, in conjunction with free iron (Fe2+), can trigger ferroptosis. Moreover, ROS contribute to protein and lipid oxidation, endothelial dysfunction, and an inflammatory response, all of which mediate secondary brain injury following IS. This review succinctly explores the mechanisms of ROS-mediated crosstalk between autophagy and ferroptosis and the detrimental impact of increased ROS on IS. It also offers novel perspectives for IS treatment strategies.
    Keywords:  Autophagy; Ferroptosis; Ischemic stroke; Neurological injury; Oxidative damage; ROS
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e28959
  64. Res Sq. 2024 Mar 29. pii: rs.3.rs-4049366. [Epub ahead of print]
    DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
    Alyssa Johnson, Cristian Ricaurte-Perez, P Wall, Olga Dubuisson, K Bohnert.
      Although life expectancy has increased, longer lifespans do not always align with prolonged healthspans and, as a result, the occurrence of age-related degenerative diseases continues to increase. Thus, biomedical research has been shifting focus to strategies that enhance both lifespan and healthspan concurrently. Two major transcription factors that have been heavily studied in the context of aging and longevity are DAF-16/FOXO and HLH-30/TFEB; however, how these two factors coordinate to promote longevity is still not fully understood. In this study, we reveal a new facet of their cooperation that supports healthier aging in C. elegans. Namely, we demonstrate that the combinatorial effect of daf-16 and hlh-30 is required to trigger robust lysosomal tubulation, which contributes to systemic health benefits in late age by enhancing cross-tissue proteostasis mechanisms. Remarkably, this change in lysosomal morphology can be artificially induced via overexpression of SVIP, a previously characterized tubular lysosome stimulator, even when one of the key transcription factors, DAF-16, is absent. This adds to growing evidence that SVIP could be utilized to employ tubular lysosome activity in adverse conditions or disease states. Mechanistically, intestinal overexpression of SVIP leads to nuclear accumulation of HLH-30 in gut and non-gut tissues and triggers global gene expression changes that promotes systemic health benefits. Collectively, our work reveals a new cellular process that is under the control of DAF-16 and HLH-30 and provides further insight into how these two transcription factors may be exerting their pro-health effects.
    DOI:  https://doi.org/10.21203/rs.3.rs-4049366/v1
  65. Cells. 2024 Mar 29. pii: 598. [Epub ahead of print]13(7):
    The ZIKV NS5 Protein Aberrantly Alters the Tubulin Cytoskeleton, Induces the Accumulation of Autophagic p62 and Affects IFN Production: HDAC6 Has Emerged as an Anti-NS5/ZIKV Factor.
    Silvia Pérez-Yanes, Iria Lorenzo-Sánchez, Romina Cabrera-Rodríguez, Jonay García-Luis, Rodrigo Trujillo-González, Judith Estévez-Herrera, Agustín Valenzuela-Fernández.
      Zika virus (ZIKV) infection and pathogenesis are linked to the disruption of neurogenesis, congenital Zika syndrome and microcephaly by affecting neural progenitor cells. Nonstructural protein 5 (NS5) is the largest product encoded by ZIKV-RNA and is important for replication and immune evasion. Here, we studied the potential effects of NS5 on microtubules (MTs) and autophagy flux, together with the interplay of NS5 with histone deacetylase 6 (HDAC6). Fluorescence microscopy, biochemical cell-fractionation combined with the use of HDAC6 mutants, chemical inhibitors and RNA interference indicated that NS5 accumulates in nuclear structures and strongly promotes the acetylation of MTs that aberrantly reorganize in nested structures. Similarly, NS5 accumulates the p62 protein, an autophagic-flux marker. Therefore, NS5 alters events that are under the control of the autophagic tubulin-deacetylase HDAC6. HDAC6 appears to degrade NS5 by autophagy in a deacetylase- and BUZ domain-dependent manner and to control the cytoplasmic expression of NS5. Moreover, NS5 inhibits RNA-mediated RIG-I interferon (IFN) production, resulting in greater activity when autophagy is inhibited (i.e., effect correlated with NS5 stability). Therefore, it is conceivable that NS5 contributes to cell toxicity and pathogenesis, evading the IFN-immune response by overcoming HDAC6 functions. HDAC6 has emerged as an anti-ZIKV factor by targeting NS5.
    Keywords:  BUZ domain; HDAC6; MT acetylation; NS5; NS5 clearance; ZIKV; aberrant MTs; autophagic p62; inhibition of IFN production; tubulin deacetylase
    DOI:  https://doi.org/10.3390/cells13070598
  66. Cancer Lett. 2024 Apr 04. pii: S0304-3835(24)00239-8. [Epub ahead of print] 216846
    XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer.
    Jiajia Wang, Pengyu Fan, Peng Shen, Cong Fan, Pan Zhao, Yao Shen, Kewei Dong, Rui Ling, Suning Chen, Jian Zhang.
      Cancer cells employ the unfolded protein response (UPR) or induce autophagy, especially selective removal of certain ER domains via reticulophagy (termed ER-phagy), to mitigate endoplasmic reticulum (ER) stress for ER homeostasis when encountering microenvironmental stress. N6-methyladenosine (m6A) is one of the most abundant epitranscriptional modifications and plays important roles in various biological processes. However, the molecular mechanism of m6A modification in the ER stress response is poorly understood. In this study, we first found that ER stress could dramatically elevate m6A methylation levels through XBP1s-dependent transcriptional upregulation of METTL3/METTL14 in breast cancer (BC) cells. Further MeRIP sequencing and relevant validation results confirmed that ER stress caused m6A methylation enrichment on target genes for ER-phagy. Mechanistically, METTL3/METTL14 increased ER-phagy machinery formation by promoting m6A modification of the ER-phagy regulators CALCOCO1 and p62, thus enhancing their mRNA stability. Of note, we further confirmed that the chemotherapeutic drug paclitaxel (PTX) could induce ER stress and increase m6A methylation for ER-phagy. Furthermore, the combination of METTL3/METTL14 inhibitors with PTX demonstrated a significant synergistic therapeutic effect in both BC cells and xenograft mice. Thus, our data built a novel bridge on the crosstalk between ER stress, m6A methylation and ER-phagy. Most importantly, our work provides novel evidence of METTL3 and METTL14 as potential therapeutic targets for PTX sensitization in breast cancer.
    Keywords:  CALCOCO1; ER stress; ER-Phagy; Paclitaxel; XBP1; m6A; p62
    DOI:  https://doi.org/10.1016/j.canlet.2024.216846
  67. Acta Neuropathol. 2024 Apr 06. 147(1): 67
    Altered TFEB subcellular localization in nigral neurons of subjects with incidental, sporadic and GBA-related Lewy body diseases.
    Tim E Moors, Martino L Morella, Cesc Bertran-Cobo, Hanneke Geut, Vinod Udayar, Evelien Timmermans-Huisman, Angela M T Ingrassia, John J P Brevé, John G J M Bol, Vincenzo Bonifati, Ravi Jagasia, Wilma D J van de Berg.
      Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson's disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation in post-mortem human brain of individuals with either incidental Lewy body disease (iLBD), GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB (sPD/DLB), compared to control subjects. We analyzed nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the TFEB subcellular localization patterns. We observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both in sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn accumulation in all groups. Importantly, we observed previously-unidentified TFEB-immunopositive perinuclear clusters in human dopaminergic neurons, which localized at the Golgi apparatus. These TFEB clusters were more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons, but also in neurons lacking detectable aSyn accumulation. In aSyn-negative cells, cytoplasmic TFEB clusters were more frequently observed in GBA-PD/DLB and iLBD patients, and correlated with reduced GBA enzymatic activity as well as increased Braak LB stage. Altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected TFEB-regulated genes, indicating a possible early dysfunction of lysosomal regulation. Overall, we observed cytoplasmic TFEB retention and accumulation at the Golgi in cells without apparent pSer129 aSyn accumulation in iLBD and PD/DLB patients. This suggests potential TFEB impairment at the early stages of cellular disease and underscores TFEB as a promising therapeutic target for synucleinopathies.
    Keywords:  Alpha-synuclein; GBA; Lewy body diseases; Lysosome; Parkinsons disease; TFEB
    DOI:  https://doi.org/10.1007/s00401-024-02707-z
  68. Nanoscale. 2024 Apr 11.
    Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.
    Xueqian Wang, Shulin Zhao, Guiqian Fang, Ran Wang, Xinxing Lyu, Xintian Shao, Peixue Ling, CaiCai Meng, Jia Chen, Yanling Mu.
      Frequently, subcellular-targeted drugs tend to accumulate in lysosomes after cellular absorption, a process termed the lysosomal trap. This accumulation often interferes with the drug's ability to bind to its target, resulting in decreased efficiency. Existing methods for addressing lysosome-induced drug resistance mainly involve improving the structures of small molecules or enveloping drugs in nanomaterials. Nonetheless, these approaches can lead to changes in the drug structure or potentially trigger unexpected reactions within organisms. To address these issues, we introduced a strategy that involves inactivating the lysosome with the use of Ag nanoparticles (Cy3.5@Ag NPs). In this method, the Cy3.5@Ag NPs gradually accumulate inside lysosomes, leading to permeation of the lysosomal membrane and subsequent lysosomal inactivation. In addition, Cy3.5@Ag NPs also significantly affected the motility of lysosomes and induced the occurrence of lysosome passivation. Importantly, coincubating Cy3.5@Ag NPs with various subcellular-targeted drugs was found to significantly increase the efficiency of these treatments. Our strategy illustrates the potential of using lysosomal inactivation to enhance drug efficacy, providing a promising therapeutic strategy for cancer.
    DOI:  https://doi.org/10.1039/d4nr00451e
  69. Int J Mol Sci. 2024 Mar 29. pii: 3806. [Epub ahead of print]25(7):
    Alterations in Proteostasis Mechanisms in Niemann-Pick Type C Disease.
    Iris Valeria Servín Muñoz, Daniel Ortuño-Sahagún, Christian Griñán-Ferré, Mercè Pallàs, Celia González-Castillo.
      Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.
    Keywords:  cholesterol; lysosomal storage diseases (LSDs); lysosome; protein degradation; protein folding
    DOI:  https://doi.org/10.3390/ijms25073806
  70. Fish Shellfish Immunol. 2024 Apr 07. pii: S1050-4648(24)00194-3. [Epub ahead of print] 109550
    STAM2 negatively regulates the MyD88-mediated NF-κB signaling pathway in miiuy croaker, Miichthys miiuy.
    Yan Xu, Wenxin Li, Ya Chen, Tianjun Xu, Yuena Sun.
      Signal transducing adapter molecule 2 (STAM2), a member of the Signal Transducing Adapter Molecule (STAM) family, is a protein with significant implications in diverse signaling pathways and endocytic membrane trafficking. However, the role of the STAM2 especially in fish, remains largely unknown. In this study, we discover that STAM2 negatively regulates the NF-κB signaling pathway, and its inhibitory effect is enhanced upon LPS induction. Our study confirms that STAM2 can enhance the degradation of Adaptor molecule myeloid differentiation primary-response protein 88 (MyD88), an upstream regulator of NF-κB pathway activation. Furthermore, the UIM domain of STAM2 is important for the inhibition of MyD88. Mechanistically, STAM2 inhibits the NF-κB signaling pathway by targeting the MyD88 autophagy pathway. In addition, we show that STAM2 promotes the proliferation of V. harveyi. In summary, our study reveals that STAM2 inhibits NF-κB signaling activation and mediates innate immunity in teleosts via the autophagy signaling pathway of MyD88.
    Keywords:  MyD88; NF-κB; STAM2; autophagy
    DOI:  https://doi.org/10.1016/j.fsi.2024.109550
  71. Redox Biol. 2024 Apr 03. pii: S2213-2317(24)00126-5. [Epub ahead of print]72 103150
    S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.
    Leire Goicoechea, Sandra Torres, Laura Fàbrega, Mónica Barrios, Susana Núñez, Josefina Casas, Gemma Fabrias, Carmen García-Ruiz, José C Fernández-Checa.
      Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1-/- mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1-/- mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1-/- mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1-/- mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.
    Keywords:  Antioxidants; Membrane fluidity; Mitochondrial GSH; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.redox.2024.103150
  72. Med Oncol. 2024 Apr 09. 41(5): 108
    Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights.
    Ahmadreza Lagzian, Marziye Askari, Melika Sadat Haeri, Nastaran Sheikhi, Sara Banihashemi, Mohsen Nabi-Afjadi, Yalda Malekzadegan.
      Oral squamous cell carcinoma (OSCC) is a cancer type with a high rate of recurrence and a poor prognosis. Tumor chemo-resistance remains an issue for OSCC patients despite the availability of multimodal therapy options, which causes an increase in tumor invasiveness. Vacuolar ATPase (V-ATPase), appears to be one of the most significant molecules implicated in MDR in tumors like OSCC. It is primarily responsible for controlling the acidity in the solid tumors' microenvironment, which interferes with the absorption of chemotherapeutic medications. However, the exact cellular and molecular mechanisms V-ATPase plays in OSCC chemo-resistance have not been understood. Uncovering these mechanisms can contribute to combating OSCC chemo-resistance and poor prognosis. Hence, in this review, we suggest that one of these underlying mechanisms is autophagy induced by V-ATPase which can potentially contribute to OSCC chemo-resistance. Finally, specialized autophagy and V-ATPase inhibitors may be beneficial as an approach to reduce drug resistance to anticancer therapies in addition to serving as coadjuvants in antitumor treatments. Also, V-ATPase could be a prognostic factor for OSCC patients. However, in the future, more investigations are required to demonstrate these suggestions and hypotheses.
    Keywords:  Autophagy; Chemo-resistance; Chemotherapy; OSCC; Oral cancer; V-ATPase
    DOI:  https://doi.org/10.1007/s12032-024-02313-9
  73. MedComm (2020). 2024 Apr;5(4): e540
    Dynamic changes in lysosome-related pathways in APP/PS1 mice with aging.
    Zhendong Xu, Jichang Hu, Zhen Wei, Yu Lei, Henok Kessete Afewerky, Yang Gao, Lu Wan, Longfei Li, Ling Lei, Yi Liu, Fang Huang, Tong Yu, Jian-Zhi Wang, Hong-Lian Li, Rong Liu, Xiaochuan Wang.
      Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age-dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age-gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β-amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age-dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age-dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age-dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age-gradient changes in the autophagy-lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state.
    Keywords:  Alzheimer's disease; Aβ; SGK1/FOXO3a pathway; autophagy–lysosome system; endosomal/lysosome system; transcriptome sequencing
    DOI:  https://doi.org/10.1002/mco2.540
  74. Development. 2024 Apr 01. pii: dev202091. [Epub ahead of print]151(7):
    Nutrient deprivation induces mouse embryonic diapause mediated by Gator1 and Tsc2.
    Jiajia Ye, Yuting Xu, Qi Ren, Lu Liu, Qiang Sun.
      Embryonic diapause is a special reproductive phenomenon in mammals that helps embryos to survive various harsh stresses. However, the mechanisms of embryonic diapause induced by the maternal environment is still unclear. Here, we uncovered that nutrient deficiency in uterine fluid was essential for the induction of mouse embryonic diapause, shown by a decreased concentration of arginine, leucine, isoleucine, lysine, glucose and lactate in the uterine fluid of mice suffering from maternal starvation or ovariectomy. Moreover, mouse blastocysts cultured in a medium with reduced levels of these six components could mimic diapaused blastocysts. Our mechanistic study indicated that amino acid starvation-dependent Gator1 activation and carbohydrate starvation-dependent Tsc2 activation inhibited mTORC1, leading to induction of embryonic diapause. Our study elucidates the essential environmental factors in diapause induction.
    Keywords:  Embryonic diapause; Gator1; Mouse; Nutrient deprivation; Tsc2
    DOI:  https://doi.org/10.1242/dev.202091
  75. Front Oncol. 2024 ;14 1364070
    Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment.
    Jingjing Ji, Xi Cheng, Rong Du, Yuanyuan Xie, Yuquan Zhang.
      Administering medication is a crucial strategy in improving the prognosis for advanced endometrial cancer. However, the rise of drug resistance often leads to the resurgence of cancer or less-than-ideal treatment outcomes. Prior studies have shown that autophagy plays a dual role in the development and progression of endometrial cancer, closely associated with drug resistance. As a result, concentrating on autophagy and its combination with medical treatments might be a novel approach to improve the prognosis for endometrial cancer. This study explores the impact of autophagy on drug resistance in endometrial cancer, investigates its core mechanisms, and scrutinizes relevant treatments aimed at autophagy, aiming to illuminate the issue of treatment resistance in advanced endometrial cancer.
    Keywords:  autophagy; chemotherapy; drug resistance; endocrine therapy; endometrial cancer
    DOI:  https://doi.org/10.3389/fonc.2024.1364070
  76. Int J Mol Sci. 2024 Apr 06. pii: 4087. [Epub ahead of print]25(7):
    The Intricate Balance between Life and Death: ROS, Cathepsins, and Their Interplay in Cell Death and Autophagy.
    Maya V Voronina, Anastasia S Frolova, Ekaterina P Kolesova, Nikita A Kuldyushev, Alessandro Parodi, Andrey A Zamyatnin.
      Cellular survival hinges on a delicate balance between accumulating damages and repair mechanisms. In this intricate equilibrium, oxidants, currently considered physiological molecules, can compromise vital cellular components, ultimately triggering cell death. On the other hand, cells possess countermeasures, such as autophagy, which degrades and recycles damaged molecules and organelles, restoring homeostasis. Lysosomes and their enzymatic arsenal, including cathepsins, play critical roles in this balance, influencing the cell's fate toward either apoptosis and other mechanisms of regulated cell death or autophagy. However, the interplay between reactive oxygen species (ROS) and cathepsins in these life-or-death pathways transcends a simple cause-and-effect relationship. These elements directly and indirectly influence each other's activities, creating a complex web of interactions. This review delves into the inner workings of regulated cell death and autophagy, highlighting the pivotal role of ROS and cathepsins in these pathways and their intricate interplay.
    Keywords:  apoptosis; autophagy; cathepsins; cell death; oxidative stress; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/ijms25074087
  77. Aging Dis. 2024 Mar 18.
    C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity.
    Kerry C Ryan, Zahra Ashkavand, Jocelyn T Laboy, Ling Wang, Margarida Barroso, Kenneth R Norman.
      Compromised lysosome function is implicated in the pathology of many neurodegenerative diseases, including Alzheimer's disease (AD). Familial Alzheimer's disease (fAD) is caused primarily by mutations in the presenilin encoding genes, but the underlying mechanism remains obscure. Loss of the conserved C. elegans presenilin orthologue SEL-12 results in increased mitochondrial calcium, which promotes neurodegeneration. Here, we find that sel-12 mutant lysosomes, independent of SEL-12 proteolytic activity, are significantly enlarged and more alkaline due to increased ER-to-mitochondrial calcium signaling and concomitant mitochondrial oxidative stress. These defects and their dependence on mitochondrial calcium are recapitulated in human fAD fibroblasts, demonstrating a conserved role for mitochondrial calcium in presenilin-mediated lysosome dysfunction. sel-12 mutants also have increased contact surface area between the ER, mitochondria, and lysosomes, suggesting sel-12 has an additional role in modulating organelle contact and communication. Overall, we demonstrate that SEL-12 maintains lysosome acidity and lysosome health by controlling ER-to-mitochondrial calcium signaling.
    DOI:  https://doi.org/10.14336/AD.2024.0228
  78. Nat Rev Neurosci. 2024 Apr 10.
    Key genes and convergent pathogenic mechanisms in Parkinson disease.
    Robert Coukos, Dimitri Krainc.
      Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.
    DOI:  https://doi.org/10.1038/s41583-024-00812-2
  79. J Exp Clin Cancer Res. 2024 Apr 13. 43(1): 112
    Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.
    Zixi Wang, Huaiyuan Zong, Weiwei Liu, Wei Lin, Anjiang Sun, Zhao Ding, Xu Chen, Xiaofeng Wan, Yanyan Liu, Zhongdong Hu, Hongbing Zhang, Hongwu Li, Yehai Liu, Dapeng Li, Sumei Zhang, Xiaojun Zha.
       BACKGROUND: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood.
    METHODS: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models.
    RESULTS: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors.
    CONCLUSIONS: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.
    Keywords:  ERO1α; Ferroptosis; SLC7A11; Tumor growth; mTOR
    DOI:  https://doi.org/10.1186/s13046-024-03039-2
  80. Int J Mol Sci. 2024 Mar 22. pii: 3604. [Epub ahead of print]25(7):
    Galectin-3 and Autophagy in Renal Acute Tubular Necrosis.
    Suhail Al-Salam, Govindan S Jagadeesh, Manjusha Sudhadevi, Javed Yasin.
      Acute kidney injury (AKI) is a public health burden with increasing morbidity and mortality rates and health care costs. Acute tubular necrosis (ATN) is the most common cause of AKI. Cisplatin (CIS) is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies such as lung, breast, ovary, testis, bladder, cervix, and head and neck cancers. Autophagy plays an important role in AKI. Galectin-3 (Gal-3) is significantly increased in renal tubules in AKI; however, its role in autophagy is not well understood. Male C57B6/J and B6.Cg-Lgals3 <tm 1 Poi>/J Gal-3 knockout (KO) mice were used to induce AKI using a CIS mouse model of ATN. Renal Gal-3 and autophagy proteins' expression were measured using standard histologic, immunofluorescent, and enzyme-linked immunosorbent assay techniques. The data were presented as the mean ± S.E. Statistically significant differences (p < 0.05) were calculated between experimental groups and corresponding control groups by one-way analysis of variance. There was a significant increase in renal concentrations of Gal-3 in the Gal-3 wild-type CIS-treated mice when compared with sham control mice. There were significantly higher concentrations of renal LC3B, ATG13, Ulk-1, Beclin, ATG5, ATG12, ATG9A, and p-AMPK in the CIS-treated Gal-3 KO mice than in the Gal-3 wild-type CIS-treated mice. Further, there were significantly higher concentrations of mTOR, p- NF-κB, beta-catenin, and p62 in the kidneys of the Gal-3 wild-type CIS-treated mice than in the Gal-3 KO CIS-treated mice. Our findings affirm the connection between Gal-3 and autophagy, revealing its central role as a connector with prosurvival signaling proteins. Gal-3 plays a pivotal role in orchestrating cellular responses by interacting with prosurvival signal pathways and engaging with autophagy proteins. Notably, our observations highlight that the absence of Gal-3 can enhance autophagy in CIS-induced ATN.
    Keywords:  acute tubular necrosis; autophagy; cell survival signals; galectin-3; kidney; macroautophagy
    DOI:  https://doi.org/10.3390/ijms25073604
  81. MicroPubl Biol. 2024 ;2024
    Proxies introduce bias in decoding TORC1 activity.
    Marco Caligaris, Claudio De Virgilio.
      The eukaryotic TORC1 kinase integrates and links nutritional, energy, and hormonal signals to cell growth and homeostasis, and its deregulation is associated with human diseases including neurodegeneration, cancer, and metabolic syndrome. Quantification of TORC1 activities in various genetic settings and defined physiological conditions generally relies on the assessment of the phosphorylation level of residues in TORC1 targets. Here we show that two commonly used TORC1 effectors in yeast, namely Sch9 and Rps6, exhibit distinct phosphorylation patterns in response to rapamycin treatment or changes in nitrogen availability, indicating that the choice of TORC1 proxies introduces a bias in decoding TORC1 activity.
    DOI:  https://doi.org/10.17912/micropub.biology.001170
  82. FEBS Lett. 2024 Apr 11.
    Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan.
    Francesca Matteini, Sara Montserrat-Vazquez, M Carolina Florian.
      Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.
    Keywords:  Cdc42; autophagy; calorie restriction; health span; lifespan; parabiosis; partial reprogramming; senolytic; stem cell aging; stem cell rejuvenation
    DOI:  https://doi.org/10.1002/1873-3468.14865
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