bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–12–15
57 papers selected by
Viktor Korolchuk, Newcastle University
  1. Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
  2. The Crosstalk between Autophagy and Nrf2 Signaling in Cancer: from Biology to Clinical Applications.
  3. Autophagy-mediated targeted protein degradation.
  4. Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
  5. LAMTOR1 regulates dendritic lysosomal positioning in hippocampal neurons through TRPML1 inhibition.
  6. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment.
  7. Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
  8. Turning garbage into gold: Autophagy in synaptic function.
  9. Interaction between coronaviruses and the autophagic response.
  10. ESCRT mediates micronucleophagy and macronucleophagy in yeast.
  11. Autophagy modulates male fertility in arabidopsis.
  12. The mechanism of acetylation-mediated fusion of lysosomes with autophagosomes in neurons after ischemic stroke.
  13. Mitophagy Regulates Kidney Diseases.
  14. Optimizing autophagy modulation for enhanced TRAIL-mediated therapy: Unveiling the superiority of late-stage inhibition over early-stage inhibition to overcome therapy resistance in cancer.
  15. A FRET Autophagy Imaging Platform by Macrocyclic Amphiphile.
  16. Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease.
  17. Exploring the Function of OPTN From Multiple Dimensions.
  18. Exploring the Connections: Autophagy, Gut Microbiota, and Inflammatory Bowel Disease Pathogenesis.
  19. USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.
  20. Rubicon regulates exosome secretion via the non-autophagic pathway.
  21. The Mycobacterium tuberculosis lipid, PDIM, inhibits the NADPH oxidase and autophagy.
  22. Non-lytic spread of poliovirus requires the nonstructural protein 3CD.
  23. Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.
  24. Activation of branched chain amino acid catabolism protects against nephrotoxic acute kidney injury.
  25. Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT.
  26. Inhibition of miR-4763-3p expression activates the PI3K/mTOR/Bcl2 autophagy signaling pathway to ameliorate cognitive decline.
  27. The TFEB activator clomiphene citrate ameliorates lipid metabolic syndrome pathology by activating lipophagy and lipolysis.
  28. FOXO1-mediated nuclear sequestration of STAT3 and AKT1 triggers FOXO3-dependent autophagic death in hypoxic granulosa cells.
  29. Recycle, Repair, Recover: The Role of Autophagy in Modulating Skeletal Muscle Repair and Post-Exercise Recovery.
  30. Targeting the mTOR Pathway in Hepatocellular Carcinoma: The Therapeutic Potential of Natural Products.
  31. TRPML1 agonist ML-SA5 mitigates uranium-induced nephrotoxicity via promoting lysosomal exocytosis.
  32. Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
  33. A crosstalk between autophagy and apoptosis in intracerebral hemorrhage.
  34. Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy.
  35. ClBeclin1 Positively Regulates Citrus Defence Against Citrus Yellow Vein Clearing Virus Through Mediating Autophagy-Dependent Degradation of ClAPX1.
  36. Janus-like behavior of intrinsically disordered regions in reticulophagy.
  37. Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis.
  38. The role and underlying mechanism of dental pulp stem cell-derived exosomal miR-31 in the treatment of osteoarthritis by targeting mTOR to enhance chondrocyte autophagy levels.
  39. Progress in the mechanism of functional dyspepsia: roles of mitochondrial autophagy in duodenal abnormalities.
  40. A tissue-specific rescue strategy reveals the local roles of autophagy in leaves and seeds for resource allocation.
  41. Role of Autophagy in Type 2 Diabetes Mellitus: The Metabolic Clash.
  42. A Mitochondria-Targeting and Peroxynitrite-Activatable Ratiometric Fluorescent Probe for Precise Tracking of Oxidative Stress-Induced Mitophagy.
  43. mTORC1 and mTORC2 Levels in Patients with Psoriasis.
  44. Autophagy in the retina affects photoreceptor synaptic plasticity and behavior.
  45. Hydrogen sulfide attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB-mediated autophagic flux.
  46. Ubiquitination of CD47 Regulates Innate Anti-Tumor Immune Response.
  47. Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
  48. Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos.
  49. TLR3 Knockdown Attenuates Pressure-Induced Neuronal Damage In Vitro.
  50. Organellar quality control crosstalk in aging-related disease: Innovation to pave the way.
  51. Physiological and Pathological Role of mTOR Signaling in Astrocytes.
  52. Branched-chain amino acids deficiency promotes diabetic cardiomyopathy by activating autophagy of cardiac fibroblasts.
  53. Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of cushing syndrome.
  54. ORP5 promotes cardiac hypertrophy by regulating the activation of mTORC1 on lysosome.
  55. Treating Niemann-Pick C lysosomal storage: approved and emerging approaches.
  56. Role of AMPK and Sirtuins in Aging Heart: Basic and Translational Aspects.
  57. Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.
  1. Autophagy. 2024 Dec 12. 1-16
    Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
    Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen.
      Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A1 or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.Abbreviation: ΔΨm: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.
    Keywords:  PI3K-AKT-MTORC1; m.3243A>G; mitochondria; mitophagy; mtDNA mutations; nutrient signaling
    DOI:  https://doi.org/10.1080/15548627.2024.2437908
  2. Int J Biol Sci. 2024 ;20(15): 6181-6206
    The Crosstalk between Autophagy and Nrf2 Signaling in Cancer: from Biology to Clinical Applications.
    Chan Shan, Yuan Wang, Yin Wang.
      Autophagy is a catabolic process that has been conserved throughout evolution, serving to degrade and recycle cellular components and damaged organelles. Autophagy is activated under various stress conditions, such as nutrient deprivation, viral infections, and genotoxic stress, and operates in conjunction with other stress response pathways to mitigate oxidative damage and maintain cellular homeostasis. One such pathway is the Nrf2-Keap1-ARE signaling axis, which functions as an intrinsic antioxidant defense mechanism and has been implicated in cancer chemoprevention, tumor progression, and drug resistance. Recent research has identified a link between impaired autophagy, mediated by the autophagy receptor protein p62, and the activation of the Nrf2 pathway. Specifically, p62 facilitates Keap1 degradation through selective autophagy, leading to the translocation of Nrf2 into the nucleus, where it transcriptionally activates downstream antioxidant enzyme expression, thus safeguarding cells from oxidative stress. Furthermore, Nrf2 regulates p62 transcription, so a positive feedback loop involving p62, Keap1, and Nrf2 is established, which amplifies the protective effects on cells. This paper aims to provide a comprehensive review of the roles of Nrf2 and autophagy in cancer progression, the regulatory interactions between the Nrf2 pathway and autophagy, and the potential applications of the Nrf2-autophagy signaling axis in cancer therapy.
    Keywords:  Autophagy; Cancer biology; Cancer therapy; Crosstalk; Nrf2 signaling
    DOI:  https://doi.org/10.7150/ijbs.103187
  3. ChemMedChem. 2024 Dec 13. e202400866
    Autophagy-mediated targeted protein degradation.
    Jinning Shao, Shangzhi Xie, Shurui Hong, Linghui Qian.
      Autophagy is an evolutionarily conserved turnover process in eukaryotes, mediating the delivery of various cellular components to lysosomes for degradation and facilitating the recycle of the breakdown products to maintain the homeostasis. By harnessing this powerful autophagy-lysosomal degradation system, strategies for targeted protein degradation (TPD) have been emerging to remove specific disease-related proteins (both intracellular and cell-surface proteins) for complete elimination of their functions, bringing new insights to drug discovery. Herein, we give a brief introduction on how autophagy works followed by a focus on available small-molecule and macromolecule-based strategies for TPD mediated by autophagy.
    Keywords:  Macromolecule Chimera; Small Molecule; Targeted Protein Degradation; autophagy
    DOI:  https://doi.org/10.1002/cmdc.202400866
  4. iScience. 2024 Dec 20. 27(12): 111384
    Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
    Robert Weil, Emmanuel Laplantine, Messaouda Attailia, Anne Oudin, Shannel Curic, Aya Yokota, Elie Banide, Pierre Génin.
      Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111384
  5. Front Cell Neurosci. 2024 ;18 1495546
    LAMTOR1 regulates dendritic lysosomal positioning in hippocampal neurons through TRPML1 inhibition.
    Jiandong Sun, Weiju Lin, Xiaoning Hao, Michel Baudry, Xiaoning Bi.
      Intracellular lysosomal trafficking and positioning are fundamental cellular processes critical for proper neuronal function. Among the diverse array of proteins involved in regulating lysosomal positioning, the Transient Receptor Potential Mucolipin 1 (TRPML1) and the Ragulator complex have emerged as central players. TRPML1, a lysosomal cation channel, has been implicated in lysosomal biogenesis, endosomal/lysosomal trafficking including in neuronal dendrites, and autophagy. LAMTOR1, a subunit of the Ragulator complex, also participates in the regulation of lysosomal trafficking. Here we report that LAMTOR1 regulates lysosomal positioning in dendrites of hippocampal neurons by interacting with TRPML1. LAMTOR1 knockdown (KD) increased lysosomal accumulation in proximal dendrites of cultured hippocampal neurons, an effect reversed by TRPML1 KD or inhibition. On the other hand, TRPML1 activation with ML-SA1 or prevention of TRPML1 interaction with LAMTOR1 using a TAT-decoy peptide induced dendritic lysosomal accumulation. LAMTOR1 KD-induced proximal dendritic lysosomal accumulation was blocked by the dynein inhibitor, ciliobrevin D, suggesting the involvement of a dynein-mediated transport. These results indicate that LAMTOR1-mediated inhibition of TRPML1 is critical for normal dendritic lysosomal distribution and that release of this inhibition or direct activation of TRPML1 results in abnormal dendritic lysosomal accumulation. The roles of LAMTOR1-TRPML1 interactions in lysosomal trafficking and positioning could have broad implications for understanding cognitive disorders associated with lysosomal pathology and calcium dysregulation.
    Keywords:  LAMP2; Ragulator; calcium; dynein; lysosomal trafficking; mTOR
    DOI:  https://doi.org/10.3389/fncel.2024.1495546
  6. Front Immunol. 2024 ;15 1506426
    Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment.
    Zhumin Cao, Ke Tian, Yincheng Ran, Haonan Zhou, Lei Zhou, Yana Ding, Xiaowei Tang.
      The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
    Keywords:  Beclin-1; apoptosis and ferroptosis; autophagy; autophagy flux; immunotherapy; mTOR
    DOI:  https://doi.org/10.3389/fimmu.2024.1506426
  7. bioRxiv. 2024 Nov 26. pii: 2024.11.24.625107. [Epub ahead of print]
    Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
    Eunice S Wang, Hannah R S Fay, Kaitlyn M Dykstra, Michael N Phelps, Matthew Johnson, Annemarie Harrigan, Marianna C Giorgi.
      Outcomes of relapsed/refractory acute myeloid leukemia (AML) are poor, and strategies to improve outcomes are urgently needed. One important factor promoting relapse and chemoresistance is the ability of AML cells to thrive in vivo within an intrinsically hypoxic bone marrow microenvironment. Here we show that human AML cells exhibit enhanced autophagy, specifically mitophagy (i.e., increased accumulation of mitochondria and decreased mitochondrial membrane potential) under hypoxia. To target this pathway, we investigated the activity of the potent chloroquine-derived autophagy inhibitor, Lys05, on human AML cells, patient samples, and patient derived xenograft models. Inhibition of autophagy by Lys05 in AML cells prevented removal of damaged mitochondria and preferentially enhanced cell death under hypoxia mirroring the marrow microenvironment. Lys05 eradicated human AML cells of all genotypes including p53 mutant cells. Lys05 treatment in primary AML xenografted mice decreased CD34+CD38- human cells and prolonged overall survival. Moreover, Lys05 overcame hypoxia-induced chemoresistance and improved the efficacy of cytarabine, venetoclax, and azacytidine in vitro and in vivo in AML models. Our results demonstrate the importance of autophagy, specifically mitophagy, as a critical survival and chemoresistance mechanism of AML cells under hypoxic marrow conditions. Therapeutic targeting of this pathway in future clinical studies for AML is warranted.
    DOI:  https://doi.org/10.1101/2024.11.24.625107
  8. Curr Opin Neurobiol. 2024 Dec 11. pii: S0959-4388(24)00099-0. [Epub ahead of print]90 102937
    Turning garbage into gold: Autophagy in synaptic function.
    Erin Marie Smith, Maeve Louise Coughlan, Sandra Maday.
      Trillions of synapses in the human brain enable thought and behavior. Synaptic connections must be established and maintained, while retaining dynamic flexibility to respond to experiences. These processes require active remodeling of the synapse to control the composition and integrity of proteins and organelles. Macroautophagy (hereafter, autophagy) provides a mechanism to edit and prune the synaptic proteome. Canonically, autophagy has been viewed as a homeostatic process, which eliminates aged and damaged proteins to maintain neuronal survival. However, accumulating evidence suggests that autophagy also degrades specific cargoes in response to neuronal activity to impact neuronal transmission, excitability, and synaptic plasticity. Here, we will discuss the diverse roles, regulation, and mechanisms of neuronal autophagy in synaptic function and contributions from glial autophagy in these processes.
    DOI:  https://doi.org/10.1016/j.conb.2024.102937
  9. Front Cell Infect Microbiol. 2024 ;14 1457617
    Interaction between coronaviruses and the autophagic response.
    Jiarong Yu, Shengqiang Ge, Jinming Li, Yongqiang Zhang, Jiao Xu, Yingli Wang, Shan Liu, Xiaojing Yu, Zhiliang Wang.
      In recent years, the emergence and widespread dissemination of the coronavirus SARS-CoV-2 has posed a significant threat to global public health and social development. In order to safely and effectively prevent and control the spread of coronavirus diseases, a profound understanding of virus-host interactions is paramount. Cellular autophagy, a process that safeguards cells by maintaining cellular homeostasis under diverse stress conditions. Xenophagy, specifically, can selectively degrade intracellular pathogens, such as bacteria, fungi, viruses, and parasites, thus establishing a robust defense mechanism against such intruders. Coronaviruses have the ability to induce autophagy, and they manipulate this pathway to ensure their efficient replication. While progress has been made in elucidating the intricate relationship between coronaviruses and autophagy, a comprehensive summary of how autophagy either benefits or hinders viral replication remains elusive. In this review, we delve into the mechanisms that govern how different coronaviruses regulate autophagy. We also provide an in-depth analysis of virus-host interactions, particularly focusing on the latest data pertaining to SARS-CoV-2. Our aim is to lay a theoretical foundation for the development of novel coronavirus vaccines and the screening of potential drug targets.
    Keywords:  SARS-CoV-2; autophagy; coronavirus; immune response; virus replication
    DOI:  https://doi.org/10.3389/fcimb.2024.1457617
  10. Biochem Biophys Res Commun. 2024 Dec 02. pii: S0006-291X(24)01638-3. [Epub ahead of print]742 151102
    ESCRT mediates micronucleophagy and macronucleophagy in yeast.
    Most Naoshia Tasnin, Yuka Takahashi, Tsuneyuki Takuma, Takashi Ushimaru.
      Endosomal sorting complex required for transport (ESCRT) is required for maintenance of nuclear functions and prevention of neurodegenerative diseases. The budding yeast Saccharomyces cerevisiae is an ideal model for studying ESCRT-dependent diseases. Nucleolar proteins are degraded by macronucleophagy and micronucleophagy after nutrient depletion and inactivation of target of rapamycin complex 1 (TORC1) kinase. Here, we show that ESCRT is critical for micronucleophagic degradation of nucleolar proteins upon TORC1 inactivation. In addition, ESCRT was also critical for rDNA condensation and nucleolar remodeling, which is necessary for proper micronucleophagic degradation of nucleolar proteins after TORC1 inactivation. On the other hand, ESCRT was dispensable for bulk macroautophagy, whereas it was also critical for macronucleophagy. Thus, ESCRT has an important role for elimination of nucleolar proteins in response to nutrient deprivation.
    Keywords:  Autophagy; ESCRT; Micronucleophagy; Nucleophagy; TORC1; macronucleophagy
    DOI:  https://doi.org/10.1016/j.bbrc.2024.151102
  11. Autophagy. 2024 Dec 11.
    Autophagy modulates male fertility in arabidopsis.
    Zhen Lu, He Yan, Hao Wang.
      Macroautophagy/autophagy is a highly conserved catabolic process in eukaryotes and plays pivotal roles in regulating male fertility and sexual reproduction. In metazoans, mutations in core ATG (autophagy related) proteins frequently result in severe defects in sperm formation and maturation, resulting in male sterility. In contrast, autophagy has traditionally been considered dispensable for reproduction in Arabidopsis thaliana, as most atg mutants can complete fertilization and produce viable progeny without apparent reproductive defects. We recently systematically re-assessed the role of autophagy in Arabidopsis male gametophyte development and fertility using atg5 and atg7 mutants, and the double mutant. These mutants exhibited partial defects in pollen germination, pollen tube growth and seed production compared to the wild type (WT). Furthermore, our findings reveal that autophagy is essential for modulating actin dynamic organization during sperm cell formation within pollen grains and for supporting pollen tube elongation. This is achieved through the selective degradation of actin depolymerizing factors ADF7 and PFN2/Profilin2. NBR1 is identified as a key receptor mediating this process. This study provides valuable insights into the evolutionary conservation and functional divergence of autophagy in modulating male fertility, highlighting distinctions between plant and mammalian systems.
    Keywords:  Actin filament; arabidopsis thaliana; autophagy; male fertility; pollen tube growth; sperm cell biogenesis
    DOI:  https://doi.org/10.1080/15548627.2024.2441305
  12. Life Sci. 2024 Dec 07. pii: S0024-3205(24)00895-6. [Epub ahead of print] 123305
    The mechanism of acetylation-mediated fusion of lysosomes with autophagosomes in neurons after ischemic stroke.
    Yu Meilin, Xiong Yajie, He Hongyun, Deng Yihao.
      Ischemic stroke is a serious cerebrovascular disease that brings a significant threat to human health [5]. Considerable factors are involved in occurrence of cerebral ischemia. Among them, autophagy is an important intracellular process that is activated after ischemic stroke, which plays a crucial role in maintaining homeostasis and survival of neurons [10]. The fusion of lysosomes with autophagosomes is a key step in autophagic processes [1]. In recent decades, investigations have found that acetylation, a common post-translational modification of proteins, has an important regulatory effect on autophagy [7]. The present article focuses on elucidating mechanism and roles of acetylation in fusion of lysosomes with autophagosomes in neurons after ischemic stroke, to seek novel targets and strategies for deeper understanding of the pathogenesis of ischemic stroke [8]. This review is also to provide clues for clinical treatment of ischemic stroke [9].
    Keywords:  Acetylation; Autophagy; Fusion of lysosomes with autophagosomes; Ischemic stroke
    DOI:  https://doi.org/10.1016/j.lfs.2024.123305
  13. Kidney Dis (Basel). 2024 Dec;10(6): 573-587
    Mitophagy Regulates Kidney Diseases.
    Xiaolu Fan, Linlin Wu, Fengqi Wang, Dong Liu, Xufeng Cen, Hongguang Xia.
       Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions.
    Summary: Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin, the main mitophagy regulatory proteins, represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials.
    Key Message: This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.
    Keywords:  Acute kidney injury; Alport syndrome; Chronic kidney disease; Mitophagy; Parkin
    DOI:  https://doi.org/10.1159/000541486
  14. Basic Clin Pharmacol Toxicol. 2025 Jan;136(1): e14110
    Optimizing autophagy modulation for enhanced TRAIL-mediated therapy: Unveiling the superiority of late-stage inhibition over early-stage inhibition to overcome therapy resistance in cancer.
    Kazi Mohammad Ali Zinnah, Ali Newaz Munna, Sang-Youel Park.
      Autophagy is a vital mechanism that eliminates large cytoplasmic components via lysosomal degradation to maintain cellular homeostasis. The role of autophagy in cancer treatment has been studied extensively. Autophagy primarily prevents tumour initiation by maintaining genomic stability and preventing cellular inflammation. However, autophagy also supports cancer cell survival and growth by providing essential nutrients for therapeutic resistance. Thus, autophagy has emerged as a promising strategy for overcoming resistance and enhancing anti-cancer therapy. Inhibiting autophagy significantly improves the sensitivity of lung, colorectal, breast, liver and prostate cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). This review investigates the intricate interplay between autophagy modulation and TRAIL-based therapy, specifically focussing on comparing the efficacy of late-stage autophagy inhibition versus early-stage inhibition in overcoming cancer resistance. We expose the distinctive advantages of late-stage autophagy inhibition by exploring the mechanisms underlying autophagy's impact on TRAIL sensitivity. Current preclinical and clinical investigations are inspected, showing the potential of targeting late-stage autophagy for sensitizing resistant cancer cells to TRAIL-induced apoptosis. This review emphasizes the significance of optimizing autophagy modulation to enhance TRAIL-mediated therapy and overcome the challenge of treatment resistance in cancer. We offer insights and recommendations for guiding the development of potential therapeutic strategies aimed at overcoming the challenges posed by treatment-resistant cancers.
    Keywords:  TRAIL; autophagy; autophagy inhibition; cancer therapy; resistance
    DOI:  https://doi.org/10.1111/bcpt.14110
  15. Angew Chem Int Ed Engl. 2024 Dec 12. e202420793
    A FRET Autophagy Imaging Platform by Macrocyclic Amphiphile.
    Ze-Tao Jiang, Jie Chen, Fang-Yuan Chen, Yuan-Qiu Cheng, Shun-Yu Yao, Rong Ma, Wen-Bo Li, Hongzhong Chen, Dong-Sheng Guo.
      Autophagy is a ubiquitous process of organelle interaction in eukaryotic cells, in which various organelles or proteins are recycled and operated through the autophagy pathway to ensure nutrient and energy homeostasis. Although numerous fluorescent probes have been developed to image autophagy, these environment-responsive probes suffer from inherent deficiencies such as inaccuracy and limited versatility. Here, we present a modular macrocyclic amphiphile Förster Resonance Energy Transfer (FRET) platform (SC6A12C/NCM, SN), constructed through the amphiphilic assembly of sulfonatocalix[6]arene (SC6A12C) with N-cetylmorpholine (NCM) for lysosome targeting. The hydrophobic fluorophore BPEA (FRET donor) was entrapped within the inner hydrophobic phase and showed strong fluorescence emission. Attributed to the broad-spectrum encapsulation of SC6A12C, three commercially available organelle probes (Mito-Tracker Red, ER Tracker Red, and RhoNox-1) were selected as SC6A12C guests (FRET acceptors). During autophagy process, the formation of intracellular host-guest complexes leads to strong FRET signal, allowing us to visualize the fusion of mitochondria, endoplasmic reticulum, and Golgi apparatus with lysosomes, respectively. This study provides a versatile and accessible platform for imaging organelle autophagy.
    Keywords:  FRET; autophagy imaging; calixarenes; macrocyclic amphiphiles; molecular recognition
    DOI:  https://doi.org/10.1002/anie.202420793
  16. Neurobiol Dis. 2024 Dec 06. pii: S0969-9961(24)00362-0. [Epub ahead of print]204 106760
    Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease.
    Hongling Zhu, Y Terry Lee, Colleen Byrnes, Jabili Angina, Danielle A Springer, Galina Tuymetova, Mari Kono, Cynthia J Tifft, Richard L Proia.
      Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function-related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases.
    Keywords:  Ganglioside; Glycosphingolipid; Lysosomal storage disease; Lysosome; Neurodegeneration; Sandhoff disease; Sphingolipid; Synaptic function; mTOR
    DOI:  https://doi.org/10.1016/j.nbd.2024.106760
  17. Cell Biochem Funct. 2024 Dec;42(8): e70029
    Exploring the Function of OPTN From Multiple Dimensions.
    Yanan Guo, Yixiao Tian, Peng Xia, Xinyue Zhou, Xiaohui Hu, Zhao Guo, Pengfei Ji, Xinyi Yuan, Daosen Fu, Keyu Yin, Rong Shen, Degui Wang.
      Autophagy is an essential intracellular degradation system responsible for delivering cytoplasmic components to lysosomes. Within this intricate process, optineurin (OPTN), an autophagy receptor, has attracted extensive attention due to its multifaceted roles in the autophagy process. OPTN is regulated by various posttranslational modifications and actively participates in numerous signaling pathways and cellular processes. By exploring the regulatory mechanism of OPTN posttranslational modification, we can further understand the critical role of protein posttranslational modification in biological progress, such as autophagy. Additionally, OPTN is implicated in many human diseases, including rheumatoid arthritis, osteoporosis, and infectious diseases. And we delve into the inflammatory pathways regulated by OPTN and clarify how it regulates inflammatory diseases and cancer. We aim to enhance the understanding of OPTN's multifaceted functions in cellular processes and its implications in the pathogenesis of inflammatory diseases and cancer.
    Keywords:  OPTN; autophagy; cancer; inflammatory diseases; posttranslational modification; signaling pathway
    DOI:  https://doi.org/10.1002/cbf.70029
  18. J Inflamm Res. 2024 ;17 10453-10470
    Exploring the Connections: Autophagy, Gut Microbiota, and Inflammatory Bowel Disease Pathogenesis.
    Arunkumar Subramanian, Afrarahamed J, Tamilanban T, Vinoth Kumarasamy, M Yasmin Begum, Mahendran Sekar, Vetriselvan Subramaniyan, Ling Shing Wong, Adel Al Fatease.
      Inflammatory Bowel Disease (IBD), which includes Crohn's disease and ulcerative colitis, represents a complex and growing global health issue with a multifaceted origin. This review delves into the intricate relationship between gut microbiota, autophagy, and the development of IBD. The gut microbiota, a diverse community of microorganisms, plays a vital role in maintaining gut health, while imbalances in this microbial community, known as dysbiosis, are linked to IBD. Autophagy, a process by which cells recycle their components, is essential for gut homeostasis and the regulation of immune responses. When autophagy is impaired and dysbiosis occurs, they individually contribute to IBD, with their combined impact intensifying inflammation. The interconnectedness of gut microbiota, autophagy, and the host's immune system is central to the onset of IBD. The review also examines how diet influences gut microbiota and its subsequent effects on IBD. It highlights the therapeutic potential of targeting the microbiota and modulating autophagic pathways as treatment strategies for IBD. Understanding these interactions could lead to personalized therapies within the rapidly advancing fields of microbiome research and immunology.
    Keywords:  Crohn’s disease; autophagy; gut microbiota; inflammatory bowel disease; ulcerative colitis
    DOI:  https://doi.org/10.2147/JIR.S483958
  19. Autophagy. 2024 Dec 11. 1-18
    USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.
    Sen Kang, Shuxin Liu, Xian Dong, Haoyu Li, Yuanyi Qian, Anna Dai, Wentao He, Xiaojun Li, Qianming Chen, Huiming Wang, Pei-Hui Ding.
      Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression. Specifically, through genomic and histological analysis of clinical gingival samples, we observed a decreased RAB7A expression and impaired autophagic activity in periodontitis. This was further substantiated through experimental periodontitis mice, where RAB7A inactivation was shown to directly affect autophagy efficiency and drive periodontitis progression. Next, we explored the function of active RAB7A to promote lysosomal trafficking dynamics and autophagosome-lysosome fusion, which was inhibited by RAB7A ubiquitination in macrophages stimulated by Porphyromonas gingivalis (P. g.), one of the keystone pathogens of periodontitis. Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo. In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.Abbreviation: 3-MA: 3-methyladenine; Baf A1:bafilomycin A1; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1β: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; P.g.: Porphyromonasgingivalis; RILP: Rabinteracting lysosomal protein; ScRNA-seq: single-cell RNA sequencing; SQSTM1/p62: sequestosome 1; S.s.: Streptococcus sanguinis; USP4:ubiquitin specific peptidase 4.
    Keywords:  Autophagy; GTP-RAB7A; IL1B; porphyromonas gingivalis; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2429371
  20. Autophagy. 2024 Dec 12. 1-3
    Rubicon regulates exosome secretion via the non-autophagic pathway.
    Kyosuke Yanagawa, Tamotsu Yoshimori.
      Exosomes are small extracellular vesicles (EVs), which have the diameter of 50-150 nm and originate from intralumenal vesicles in multivesicular endosomes (MVBs). Exosomes secreted from donor cells are delivered to recipient cells for transferring of exosome cargos, such as proteins, lipids and nucleic acids. The cargo transfer by exosomes has a pivotal role in cell-to-cell communication for many cellular processes; however, the detailed mechanism remains largely elusive. In our recent study, we found that RUBCN/rubicon regulates exosome secretion through endosomal recruitment of WIPI2, which promotes ESCRT-dependent MVB formation. We further showed that this pathway is essential for age-dependent increasing of exosomes, which transfer the pro-senescent microRNAs, including Mir26a and Mir486a, and accelerate cellular senescence in the recipient cells. Our findings highlight RUBCN's key role in exosome secretion and its impact on cellular senescence, providing insights into its potential contributions to aging.
    Keywords:  Aging; autophagy; exosome; extracellular vesicle; microRNA; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2437653
  21. Autophagy. 2024 Dec 11.
    The Mycobacterium tuberculosis lipid, PDIM, inhibits the NADPH oxidase and autophagy.
    Ekansh Mittal, Jennifer A Philips.
      Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), remains a significant global health challenge. Mtb is transmitted by respiratory aerosols and infects a variety of myeloid populations. Our recent study shows that the Mtb virulence lipid phthiocerol dimycocerosate (PDIM) promotes the intracellular survival of Mtb in macrophages by inhibiting NADPH oxidase, thereby impairing LC3-associated phagocytosis, and in vivo PDIM also antagonizes canonical macroautophagy/autophagy. In addition, mice defective in autophagy in myeloid cells fail to develop B-cell follicles in the lungs during chronic infection. Here, we present a summary of our recent publication, highlighting the most significant findings and discussing how they provide new insight into the role of autophagy and the diversity of lung myeloid cells in the pathogenesis of Mtb.
    Keywords:  B cells; LC3-associated phagocytosis; macrophages; phthiocerol dimycocerosate; tertiary lymphoid follicle
    DOI:  https://doi.org/10.1080/15548627.2024.2439928
  22. mBio. 2024 Dec 12. e0327624
    Non-lytic spread of poliovirus requires the nonstructural protein 3CD.
    David Aponte-Diaz, Jayden M Harris, Tongjia Ella Kang, Victoria Korboukh, Mohamad S Sotoudegan, Jennifer L Gray, Neela H Yennawar, Ibrahim M Moustafa, Andrew Macadam, Craig E Cameron.
      Non-enveloped viruses like poliovirus (PV) have evolved the capacity to spread by non-lytic mechanisms. For PV, this mechanism exploits the host secretory autophagy pathway. Virions are selectively incorporated into autophagosomes, double-membrane vesicles that travel to the plasma membrane, fuse, and release single-membrane vesicles containing virions. Loading of cellular cargo into autophagosomes relies on direct or indirect interactions with microtubule-associated protein 1B-light chain 3 (LC3) that are mediated by motifs referred to as LC3-interaction regions (LIRs). We have identified a PV mutant with a severe defect in non-lytic spread. An F-to-Y substitution in a putative LIR of the nonstructural protein 3CD prevented virion incorporation into LC3-positive autophagosomes and virion trafficking to the plasma membrane for release. Using high-angle annular dark-field scanning transmission electron microscopy to monitor PV-induced autophagosome biogenesis, for the first time, we show that virus-induced autophagic signals yield normal autophagosomes, even in the absence of virions. The F-to-Y derivative of PV 3CD was unable to support normal autophagosome biogenesis. Together, these studies make a compelling case for the direct role of a viral nonstructural protein in the formation and loading of the vesicular carriers used for non-lytic spread that may depend on the proper structure, accessibility, and/or dynamics of its LIR. The studies of PV 3CD protein reported here will hopefully provoke a more deliberate look at the presence and function of LIR motifs in viral proteins of viruses known to use autophagy as the basis for non-lytic spread.
    IMPORTANCE: Poliovirus (PV) and other enteroviruses hijack the cellular secretory autophagy pathway for non-lytic virus transmission. While much is known about the cellular factors required for non-lytic transmission, much less is known about viral factors contributing to transmission. We have discovered a PV nonstructural protein required for multiple steps of the pathway leading to vesicle-enclosed virions. This discovery should facilitate the identification of the specific steps of the cellular secretory autophagy pathway and corresponding factors commandeered by the virus and may uncover novel targets for antiviral therapy.
    Keywords:  GABARAP; LC3; LIR; autophagy; cell membranes; enterovirus; non-lytic spread; poliovirus; replication organelles
    DOI:  https://doi.org/10.1128/mbio.03276-24
  23. Autophagy. 2024 Dec 11.
    Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.
    Karla Alvarez-Valadez, Allan Sauvat, Julien Diharce, Marion Leduc, Gautier Stoll, Lionel Guittat, Flavia Lambertucci, Juliette Paillet, Omar Motino, Lucille Ferret, Alexandra Muller, Sabrina Forveille, Maria Chiara Maiuri, Oliver Kepp, Alexandre G de Brevern, Harald Wodrich, Jonathan G Pol, Guido Kroemer, Mojgan Djavaheri-Mergny.
      Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.
    Keywords:  Autophagy; NPC intracellular cholesterol transporter 1 and 2; TFEB; cancer; lipid transport; lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1080/15548627.2024.2440842
  24. Am J Physiol Renal Physiol. 2024 Dec 09.
    Activation of branched chain amino acid catabolism protects against nephrotoxic acute kidney injury.
    Samaneh DiMartino, Monica P Revelo, Sandeep K Mallipattu, Sian E Piret.
      Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD), and there are currently no therapies for AKI. Proximal tubules (PT) are particularly susceptible to AKI, including due to nephrotoxins such as aristolochic acid I (AAI). Normal PT utilize fatty acid oxidation and branched chain amino acid (BCAA; valine, leucine, isoleucine) catabolism to generate ATP; however, in AKI, these pathways are downregulated. Our aim was to investigate the utility of a pharmacological activator of BCAA catabolism, BT2, in preventing nephrotoxic AKI. Mice were administered two injections of AAI 3 days apart to induce AKI, with or without daily BT2 treatment. Mice treated with BT2 had significantly protected kidney function (reduced serum creatinine and urea nitrogen), reduced histological injury, preservation of PT (Lotus lectin staining), and less PT injury (cytokeratin-20 staining) and inflammatory gene expression compared to mice with AAI alone. Mice with AKI had increased circulating BCAA and accumulation of BCAA in the kidney cortex. Leucine is a potent activator of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and mTORC1 signaling was activated in mice treated with AAI. However, BT2 reduced kidney cortical BCAA accumulation, and attenuated the mTORC1 signaling. In vitro, injured primary PT cells had compromised mitochondrial bioenergetics, but cells treated with AAI+BT2 had partially restored mitochondrial bioenergetics, and improved injury markers compared to cells treated with AAI alone. Thus, pharmacological activation of BCAA catabolism using BT2 attenuated nephrotoxic AKI in mice.
    Keywords:  Acute kidney injury; branched chain amino acids; cellular metabolism; proximal tubule
  25. Angiogenesis. 2024 Dec 11. 28(1): 6
    Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT.
    Antonio Queiro-Palou, Yi Jin, Lars Jakobsson.
      Arteriovenous malformations (AVMs) are abnormal high flow shunts between arteries and veins with major negative impact on the cardiovascular system. Inherited loss-of-function (LOF) mutations in endoglin, encoding an endothelial cell (EC) expressed co-receptor for BMP9/10, causes the disease HHT1/Osler-Weber-Rendu, characterized by bleeding and AVMs. Here we observe increased activity of the downstream signalling complex mTORC1 within the retinal vasculature of HHT mouse models. To investigate its importance in AVM biology, concerning subvascular action, cell specificity, signalling strength and kinetics we combine timed genetic and antibody-based models of HHT with genetic mTORC1 inhibition or activation through EC specific deletion of Rptor or Tsc1. Results demonstrate that EC mTORC1 activation is secondary to endoglin LOF and mainly a consequence of systemic effects following AVM. While genetic EC inhibition of mTORC1 only showed tendencies towards reduced AVM severity, EC overactivation counterintuitively reduced it, implying that mTORC1 must be within a certain range to facilitate AVM. Complete inhibition of mTORC1 signalling by rapamycin provided the strongest therapeutic effect, pointing to potential involvement of RAPTOR-independent pathways or AVM-promoting effects of non-ECs in this pathology.
    Keywords:  Arteriovenous malformation; Endoglin; Endothelial; HHT; Raptor; Tsc1; mTORC1
    DOI:  https://doi.org/10.1007/s10456-024-09961-5
  26. Int J Biol Sci. 2024 ;20(15): 5999-6017
    Inhibition of miR-4763-3p expression activates the PI3K/mTOR/Bcl2 autophagy signaling pathway to ameliorate cognitive decline.
    Wenxin Qi, Yiwei Ying, Peiru Wu, Naijun Dong, Wenjun Fu, Qian Liu, Natalie Ward, Xin Dong, Robert Chunhua Zhao, Jiao Wang.
      Cognitive decline and memory impairment are subsequently result in neuronal apoptosis and synaptic damage. Aberrant regulation of microRNAs has been implicated in the pathogenesis of Alzheimer's disease (AD) and may play a pivotal role in the early stages of the disease. In this study, we identified the critical role of miR-4763-3p in AD pathogenesis, focusing on early-stage mild cognitive impairment (AD-MCI). Leveraging fluorescence in situ hybridization, we observed miR-4763-3p upregulation in AD hippocampal tissue, colocalizing with Aβ and Tau. Antagomir-mediated inhibition of miR-4763-3p ameliorated cognitive decline in AD-MCI mice. RNA-seq and functional assays revealed that miR-4763-3p targets ATP11A, and antagomir enhancing inward flipping of the "eat me" phosphatidylserine signal on the surface of neuronal cells, autophagy, and clearance of Aβ/lipofuscin, while reducing neuroinflammation and neuronal apoptosis. Mechanistically, miR-4763-3p modulates the PI3K/AKT/mTOR/Bcl2 pathway, thereby promoting neuronal autophagy and reducing apoptotic crosstalk. These findings underscore miR-4763-3p as a therapeutic target for AD-MCI, offering a novel strategy to enhance neuronal autophagy, alleviate inflammation, and improve cognitive function.
    Keywords:  AD-MCI; apoptosis; autophagy; phosphatidylserine
    DOI:  https://doi.org/10.7150/ijbs.103225
  27. Biochem Pharmacol. 2024 Dec 04. pii: S0006-2952(24)00695-6. [Epub ahead of print]232 116694
    The TFEB activator clomiphene citrate ameliorates lipid metabolic syndrome pathology by activating lipophagy and lipolysis.
    Lu Li, Jieru Lin, Chunhuan Huang, Jiamiao Liu, Yi Yuan, Zhenxing Liu, Yuyin Li, Wei Li, Aipo Diao.
      The balance between lipid synthesis and lipid catabolism is critical to maintain energy homeostasis. Lipophagy and lipolysis are two important pathways for lipid selective catabolism. Defects in lipophagy and lipolysis are linked to lipid metabolic diseases. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis, as well as lipid metabolism by promoting expression of genes encoding fat catabolic lipases. Therefore, targeting TFEB provides a novel potential strategy for the treatment of lipid metabolic diseases. In this study, we showed that the TFEB activator clomiphene citrate (CC) activated the autophagy-lysosome and lipolysis pathways, and promoted degradation of lipid droplets induced by the free fatty acids oleate and palmitate in HepG2 cells. Moreover, CC treatment promoted lipid catabolism and attenuated obesity, restored lipid levels, blood glucose levels and insulin resistance, hepatocellular injury and hepatic steatosis, as well as liver inflammation in the HFD fed mice. In addition, we found that En-CC, a trans-isomer of CC, displayed less toxicity and more efficient activation of TFEB. Consistent with CC, En-CC treatment improved lipid metabolic syndrome pathology. These findings demonstrate that CC promotes clearance of lipids and ameliorates HFD-induced lipid metabolic syndrome pathology through activating TFEB-mediated lipophagy and lipolysis, indicating that CC has the potential to be used to treat lipid metabolic diseases.
    Keywords:  Autophagy; Clomiphene citrate; Hepatic steatosis; Lipolysis; Obesity; TFEB
    DOI:  https://doi.org/10.1016/j.bcp.2024.116694
  28. Int J Biol Sci. 2024 ;20(15): 5939-5958
    FOXO1-mediated nuclear sequestration of STAT3 and AKT1 triggers FOXO3-dependent autophagic death in hypoxic granulosa cells.
    Chengyu Li, Gang Wu, Caibo Ning, Zhaojun Liu, Jingli Tao, Xiumei Lu, Ming Shen, Honglin Liu.
      FOXO proteins, especially FOXO1 and FOXO3, are recognized for their roles in controlling apoptosis and autophagy. Both apoptosis and autophagy have been induced in granulosa cells (GCs) by hypoxic conditions in ovarian follicles; however, the exact contribution of FOXO proteins and autophagy to the regulation of GCs apoptosis under hypoxia remains unclear. In this investigation of porcine GCs, we reveal that FOXO1 promotes apoptosis in response to hypoxia through FOXO3-dependent autophagy. We describe how mechanistically, FOXO1 forms a complex with the transcription factor STAT3 during hypoxia. Guided by FOXO1, this complex undergoes nuclear translocation and effectively attaches to the STAT3-responsive element (SRE) located in the FOXO3 promoter region, thereby enhancing the transcriptional expression of FOXO3. Simultaneously, FOXO1 associates with AKT1, thus facilitating its nuclear entry and subsequently reducing the Ser253 phosphorylation of FOXO3, leading to FOXO3 detachment from 14-3-3 and promoting FOXO3 translocation into the nucleus. FOXO3 subsequently stimulates the upregulation of ATG3, ultimately initiating autophagy and autophagy-dependent apoptosis. Our results suggest that hypoxia acts through FOXO1 to induce autophagic death in porcine GCs by promoting the expression and nuclear import of FOXO3.
    Keywords:  AKT1; Autophagic death; FOXO1; FOXO3; Granulosa cells; Hypoxia; STAT3
    DOI:  https://doi.org/10.7150/ijbs.101309
  29. Biosci Rep. 2024 Dec 13. pii: BSR20240137. [Epub ahead of print]
    Recycle, Repair, Recover: The Role of Autophagy in Modulating Skeletal Muscle Repair and Post-Exercise Recovery.
    Jordan Acheson, Sophie Joanisse, Craig Sale, Nathan Hodson.
      Skeletal muscle is a highly plastic tissue which can adapt relatively rapidly to a range of stimuli. In response to novel mechanical loading, e.g. unaccustomed resistance exercise, myofibers are disrupted and undergo a period of ultrastructural remodelling to regain full physiological function, normally within 7 days. The mechanisms which underpin this remodelling are believed to be a combination of cellular processes including UPS/Calpain-mediated degradation, immune cell infiltration and satellite cell proliferation/differentiation. A relatively understudied cellular system which has the potential to be a significant contributing mechanism to repair and recovery is autophagolysosomal system, a cellular process which degrades damaged and dysfunctional cellular components to provide constituent components for the resynthesis of new organelles and cellular structures. This review summarises our current understanding of the autophagolysosomal system in the context of skeletal muscle repair and recovery. In addition, we also provide hypothetical models of how this system may interact with other processes involved in skeletal muscle remodelling and provide avenues for future research to improve our understanding of autophagy in human skeletal muscle.
    Keywords:  autophagy; damage; exercise; recovery; skeletal muscle
    DOI:  https://doi.org/10.1042/BSR20240137
  30. J Inflamm Res. 2024 ;17 10421-10440
    Targeting the mTOR Pathway in Hepatocellular Carcinoma: The Therapeutic Potential of Natural Products.
    Guo Chen, Ya Zhang, Yaqiao Zhou, Hao Luo, Hongzhi Guan, Baiping An.
      Despite advancements in cancer treatment through surgery and drugs, hepatocellular carcinoma (HCC) remains a significant challenge, as reflected by its low survival rates. The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating the cell cycle, proliferation, apoptosis, and metabolism. Notably, dysregulation leading to the activation of the mTOR signaling pathway is common in HCC, making it a key focus for in-depth research and a target for current therapeutic strategies. This review focuses on the role of the mTOR signaling pathway and its downstream effectors in regulating HCC cell proliferation, apoptosis, autophagy, cell cycle, and metabolic reprogramming. Moreover, it emphasizes the potential of natural products as modulators of the mTOR signaling pathway. When incorporated into combination therapies, these natural products have been demonstrated to augment therapeutic efficacy and surmount drug resistance. These products target key signaling pathways such as mTOR signaling pathways. Examples include 11-epi-sinulariolide acetate, matrine, and asparagus polysaccharide. Their inhibitory effects on these processes suggest valuable directions for the development of more effective HCC therapeutic strategies. Various natural products have demonstrated the ability to inhibit mTOR signaling pathway and suppress HCC progression. These phytochemicals, functioning as mTOR signaling pathway inhibitors, hold great promise as potential anti-HCC agents, especially in the context of overcoming chemoresistance and enhancing the outcomes of combination therapies.
    Keywords:  hepatocellular carcinoma; mTOR signaling pathway; natural products
    DOI:  https://doi.org/10.2147/JIR.S501270
  31. Biomed Pharmacother. 2024 Dec 07. pii: S0753-3322(24)01614-7. [Epub ahead of print]181 117728
    TRPML1 agonist ML-SA5 mitigates uranium-induced nephrotoxicity via promoting lysosomal exocytosis.
    Hongjing Zhang, Yifei Wang, Ruiyun Wang, Xuxia Zhang, Honghong Chen.
      Uranium (U) released from U mining and spent nuclear fuel reprocessing in the nuclear industry, nuclear accidents and military activities as a primary environmental pollutant (e.g., drinking water pollution) is a threat to human health. Kidney is one of the main target organs for U accumulation, leading to nephrotoxicity mainly associated with the injuries in proximal tubular epithelial cells (PTECs). Transient receptor potential mucolipin 1 (TRPML1) is a novel therapeutic target for nephrotoxicity caused by acute or chronic U poisoning. We herein investigate the therapeutic efficacy of ML-SA5, a small molecule agonist of TRPML1, in U-induced nephrotoxicity in acute U intoxicated mice. We demonstrate that delayed treatment with ML-SA5 enhances U clearance from the kidneys via urine excretion by activating lysosomal exocytosis, and thereby attenuates U-induced kidney dysfunction and cell death/apoptosis of renal PTECs in acute U intoxicated mice. In addition, ML-SA5 promotes the nuclear translocation of transcription factor EB (TFEB) in renal PTECs in acute U intoxicated mice. Mechanistically, ML-SA5 triggers the TRPML1-mediated lysosomal calcium release and consequently induces TFEB activation in U-loaded renal PTECs-derived HK-2 cells. Moreover, knockdown of TRPML1 or TFEB abolishes the effects of ML-SA5 on the removal of intracellular U and reduction of the cellular injury/death in U-loaded HK-2 cells. Our findings indicate that pharmacological activation of TRPML1 is a promising therapeutic approach for the delayed treatment of U-induced nephrotoxicity via the activation of the positive feedback loop of TRPML1 and TFEB and consequent the induction of lysosomal exocytosis.
    Keywords:  Decorporation; Lysosomal exocytosis; ML-SA5; Nephrotoxicity; TRPML1; Uranium
    DOI:  https://doi.org/10.1016/j.biopha.2024.117728
  32. bioRxiv. 2024 Nov 26. pii: 2024.11.25.625249. [Epub ahead of print]
    Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
    Arunkumar Venkatesan, Marc Ridilla, Nileyma Castro, J Mario Wolosin, Jessica L Henty-Ridilla, Barry E Knox, Preethi S Ganapathy, Jamin S Brown, Anthony F DeVincentis, Sandra Sieminski, Audrey M Bernstein.
      Exfoliation Syndrome (XFS) is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG), a secondary open-angle glaucoma. XFG is a complex, multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as altered cellular processes with increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from Normal (No Glaucoma) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species (ROS) accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with an increase in mitochondrial localization to lysosomes and slowed mitophagy flux. Mitochondrial dysfunction in the XFG TFs was associated with an increase in the dynamics of the microtubule cytoskeleton, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, NAD + precursor, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate abnormal mitochondria in XFG TFs and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.
    DOI:  https://doi.org/10.1101/2024.11.25.625249
  33. Front Cell Neurosci. 2024 ;18 1445919
    A crosstalk between autophagy and apoptosis in intracerebral hemorrhage.
    Moyan Wang, Xin Chen, Shuangyang Li, Lingxue Wang, Hongmei Tang, Yuting Pu, Dechou Zhang, Bangjiang Fang, Xue Bai.
      Intracerebral hemorrhage (ICH) is a severe condition that devastatingly harms human health and poses a financial burden on families and society. Bcl-2 Associated X-protein (Bax) and B-cell lymphoma 2 (Bcl-2) are two classic apoptotic markers post-ICH. Beclin 1 offers a competitive architecture with that of Bax, both playing a vital role in autophagy. However, the interaction between Beclin 1 and Bcl-2/Bax has not been conjunctively analyzed. This review aims to examine the crosstalk between autophagy and apoptosis in ICH by focusing on the interaction and balance of Beclin 1, Bax, and Bcl-2. We also explored the therapeutic potential of Western conventional medicine and traditional Chinese medicine (TCM) in ICH via controlling the crosstalk between autophagy and apoptosis.
    Keywords:  Bax; Bcl-2; apoptosis; autophagy; cerebral hemorrhage
    DOI:  https://doi.org/10.3389/fncel.2024.1445919
  34. Cell Rep. 2024 Dec 06. pii: S2211-1247(24)01403-7. [Epub ahead of print]43(12): 115052
    Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy.
    Rudy G Jacquet, Fernando González Ibáñez, Katherine Picard, Lucy Funes, Mohammadparsa Khakpour, Gunnar K Gouras, Marie-Ève Tremblay, Frederick R Maxfield, Santiago Solé-Domènech.
      How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both required for the formation of the compartments. Finally, we show that small fibrils of Aβ previously internalized and trafficked to lysosomes are exocytosed toward large Aβ aggregates by microglia. Thus, the release of lysosomal contents during digestive exophagy may also contribute to the spread and growth of fibrillar Aβ.
    Keywords:  5xFAD; Alzheimer’s disease; CP: Neuroscience; acid phosphatase; amyloid-beta; digestive exophagy; electron microscopy; extracellular degradation; lysosomal pH; lysosome; microglia
    DOI:  https://doi.org/10.1016/j.celrep.2024.115052
  35. Mol Plant Pathol. 2024 Dec;25(12): e70041
    ClBeclin1 Positively Regulates Citrus Defence Against Citrus Yellow Vein Clearing Virus Through Mediating Autophagy-Dependent Degradation of ClAPX1.
    Jiajun Wang, Ling Yu, Jinfa Zhao, Shimin Fu, Yalin Mei, Binghai Lou, Yan Zhou.
      Autophagy, one of the most widespread and highly conserved protein degradation systems in eukaryotic cells, plays an important role in plant growth, development and stress response. Beclin 1 is a core component of the phosphatidylinositol 3-kinase (PI3K) autophagy complex and positively regulates plant immunity against viruses. The upregulation of Eureka lemon ClBeclin1 was observed in response to citrus yellow vein clearing virus (CYVCV) infection. However, the function of ClBeclin1 and the underlying mechanism during CYVCV colonisation remain unclear. Here, the resistance evaluation of the overexpression and silencing of ClBeclin1 in Eureka lemon hairy roots revealed it as a positive regulator of citrus immunity against CYVCV. Transcriptomic profiling and metabolic analyses along with genetic evidence implied that the overexpression of ClBeclin1 positively triggered reactive oxygen species (ROS)- and jasmonic acid (JA)-mediated immunity in citrus. The accumulation of ROS and JA contents was attributed to the autophagic degradation of the ROS scavenger ClAPX1 via ClBeclin1 overexpression. Exogenous application of either H2O2 or JA significantly reduced CYVCV colonisation and vein-clearing symptoms on the host. Collectively, our findings indicate that ClBeclin1 activation contributes to citrus immunity against CYVCV through triggering ROS- and JA-mediated defence responses, and the accumulation of ROS and JA resulted from the autophagic degradation of ClAPX1 by ClBeclin1.
    Keywords:   Citrus yellow vein clearing virus ; ClAPX1 protein; ClBeclin1 protein; autophagy; jasmonic acid (JA); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1111/mpp.70041
  36. Autophagy. 2024 Dec 09.
    Janus-like behavior of intrinsically disordered regions in reticulophagy.
    Sergio Alejandro Poveda Cuevas, Kateryna Lohachova, Borna Markusic, Ivan Dikic, Gerhard Hummer, Ramachandra Bhaskara.
      Intrinsically disordered regions (IDRs) are crucial to homeostatic and organellar remodeling pathways. In reticulophagy/ER-phagy, long cytosolic IDR-containing receptors (e.g. RETREG1/FAM134B) house the LC3-interacting region (LIR) motif to recruit the phagophore. The precise functions of the IDR beyond engaging the autophagic machinery are unclear. Here, we comment on the role of the RETREG1-IDR based on our recent computer modeling and molecular dynamics (MD) simulations. Extensive analysis of the RETREG1-IDR indicates a continuum of conformations between expanded and compact structures, displaying a Janus-like feature. Using an adapted MARTINI model, we find that the IDR ensemble properties vary widely depending on the membrane anchor. IDRs alone are sufficient to promote and sense membrane curvature and can act as entropic tethers. When anchored to the RHD, they adopt compact collapsed conformations, acting as effector scaffolds that amplify RHD membrane remodeling properties, enhancing receptor-clustering and accelerating spontaneous budding. These findings expand the operational scope of IDRs within reticulophagy, offering fresh insights into a mechanistic understanding of membrane remodeling.
    Keywords:  Conformational heterogeneity; ER remodeling; IDRs; curvature induction; effector; entropic chain
    DOI:  https://doi.org/10.1080/15548627.2024.2437652
  37. Int J Biol Macromol. 2024 Dec 05. pii: S0141-8130(24)09289-4. [Epub ahead of print]286 138478
    Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis.
    Min Pan, Ling Zhang, Shuang Chang, Xueqin Jiang, Jiapan Shen, Xiaoxia Feng, Fangzhou Xu, Xiaojun Zha, Xu Chen, Xiaoyun Fan.
      Eosinophils play a featured role among inflammatory cells participating in the onset and development of asthma. Activated eosinophils release several cytotoxic granular proteins, such as major basic protein (MBP), posing a significant threat to airway epithelium. Ferroptosis, a novel form of cell death, is gaining recognition for its involvement in asthma pathogenesis, though the specific mechanisms remain largely unknown. Herein, we revealed that poly-l-arginine (PLA), an MBP mimic, induced ferroptosis in airway epithelium by downregulating γ-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1). Reduced GABARAPL1 expression was further confirmed in ovalbumin (OVA)-induced asthma mice and PLA-treated human airway organoids (hAOs). Mechanistically, PLA activated mechanistic target of rapamycin complex 1 (mTORC1) signaling, inhibiting pre-B-cell leukemia transcription factor 1 (PBX1), which in turn leads to transcriptional downregulation of GABARAPL1. Furthermore, MBP extracted from eosinophils, similar to PLA, induced ferroptosis in airway epithelial cells, as well as modulating mTORC1/PBX1/GABARAPL1 pathway. Finally, Ferrostatin-1 treatment or GABARAPL1 overexpression alleviated ferroptosis and airway inflammation in asthmatic mice. Overall, our findings highlight the cell communication between eosinophils and airway epithelial cells. MBP modulates the mTORC1/PBX1/GABARAPL1 axis, thereby serving as a significant contributor to ferroptosis in airway epithelium and airway inflammation. This suggests that suppressing ferroptosis in airway epithelium or targeting eosinophils and MBP could lead to novel therapeutic strategies for asthma management.
    Keywords:  Airway inflammation; Asthma; Eosinophil; Ferroptosis; Poly-l-arginine; γ-aminobutyric acid receptor-associated protein-like
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138478
  38. Arch Med Sci. 2024 ;20(5): 1680-1694
    The role and underlying mechanism of dental pulp stem cell-derived exosomal miR-31 in the treatment of osteoarthritis by targeting mTOR to enhance chondrocyte autophagy levels.
    Guanglei Zhao, Jinyang Lyu, Xin Huang, Gangyong Huang, Feiyan Chen, Yibing Wei, Siqun Wang, Jun Xia, Jie Chen, Jingsheng Shi.
       Introduction: Osteoarthritis is the most prevalent progressive musculoskeletal disease. It leads to functional impairment and decreased quality of life. However, the current treatments remain unsatisfactory. Recent studies have revealed that exosomes derived from mesenchymal stem cells offer a promising approach to improve the pathological changes in osteoarthritis, cartilage tissue, and chondrocyte homeostasis.
    Material and methods: In this in vitro and in vivo study, we studied the effects and mechanisms of dental pulp stem cell-derived exosomes (DPSC-exosomes) on osteoarthritis in a mouse model.
    Results: The study findings showed that a dental pulp stem cell could generate typical characteristic exosomes. The injection of DPSC-exosomes ameliorated destruction of cartilage, promoted matrix synthesis, inhibited cell apoptosis, and decreased the expression of catabolic factors. However, this effect was shown to be almost eliminated when miR-31 antagomir was injected.
    Conclusions: Furthermore, DPSC-exosomes show an ability to promote autophagy in chondrocytes through mTOR inhibition, in addition to reducing the mTOR luciferase activity. The ability of DPSC-exosomes to partially regulate autophagy was blocked upon inhibition of miR-31. In brief, DPSC-exosomes have a chondroprotective role in a mouse osteoarthritis model. The underlying mechanism is possibly related to miR-31-mediated suppression of the mTOR-autophagy pathway.
    Keywords:  autophagy; dental pulp; exosome; mTOR; osteoarthritis; stem cells
    DOI:  https://doi.org/10.5114/aoms/157032
  39. Front Med (Lausanne). 2024 ;11 1491009
    Progress in the mechanism of functional dyspepsia: roles of mitochondrial autophagy in duodenal abnormalities.
    Kexin Zhong, Xiaojuan Du, Yuanyuan Niu, Zhengju Li, Yongbiao Tao, Yuqian Wu, Ruiting Zhang, Linjing Guo, Yurong Bi, Lijuan Tang, Tianyu Dou, Longde Wang.
      Mitochondria are the main source of energy for cellular activity. Their functional damage or deficiency leads to cellular deterioration, which in turn triggers autophagic reactions. Taking mitochondrial autophagy as a starting point, the present review explored the mechanisms of duodenal abnormalities in detail, including mucosal barrier damage, release of inflammatory factors, and disruption of intracellular signal transduction. We summarized the key roles of mitochondrial autophagy in the abnormal development of the duodenum and examined the in-depth physiological and pathological mechanisms involved, providing a comprehensive theoretical basis for understanding the pathogenesis of functional dyspepsia. At present, it has been confirmed that an increase in the eosinophil count and mast cell degranulation in the duodenum can trigger visceral hypersensitive reactions and cause gastrointestinal motility disorders. In the future, it is necessary to continue exploring the molecular mechanisms and signaling pathways of mitochondrial autophagy in duodenal abnormalities. A deeper understanding of mitochondrial autophagy provides important references for developing treatment strategies for functional dyspepsia, thereby improving clinical efficacy and patient quality of life.
    Keywords:  duodenal abnormalities; functional dyspepsia; gastrointestinal dysfunction; mitochondrial autophagy; pathogenesis
    DOI:  https://doi.org/10.3389/fmed.2024.1491009
  40. Plant Physiol. 2024 Dec 11. pii: kiae647. [Epub ahead of print]
    A tissue-specific rescue strategy reveals the local roles of autophagy in leaves and seeds for resource allocation.
    Anne Marmagne, Fabien Chardon, Céline Masclaux-Daubresse.
      Autophagy is a vesicular mechanism that plays a fundamental role in nitrogen remobilization from senescing leaves to seeds. The Arabidopsis (Arabidopsis thaliana) autophagy (atg) mutants exhibit early senescence, reduced biomass and low seed yield. The atg seeds also exhibit major changes in N and C concentrations. During plant development, autophagy genes are expressed in the source leaves and in the sink seeds during maturation. We thus addressed the question of whether the seed composition defects in atg mutants are caused by defective N remobilization from source leaves, or whether they are due to the absence of autophagy in seeds during maturation. To answer this question, we restored autophagy activity in the atg5 mutant by expressing the wild-type ATG5 allele specifically in source leaves using the senescence-associated gene 12 (SAG12) promoter or specifically in seeds using the Glycinin-1 promoter, or in both organs using both constructs. In atg5, N remobilization from the rosettes to seeds was almost completely re-established when transformed with the pSAG12::ATG5 construct. However, transformation with the pSAG12::ATG5 construct only partially restored seed composition. In contrast, seed N and C composition was largely restored by transformation with the pGly::ATG5 construct, even though the early leaf senescence phenotype was maintained in the atg5 background. Co-transformation with pSAG12::ATG5 and pGly::ATG5 completely restored the wild-type remobilization and seed composition phenotypes. Our results highlight the essential role of autophagy in leaves for nitrogen supply and in seeds for the establishment of carbon and nitrogen reserves.
    DOI:  https://doi.org/10.1093/plphys/kiae647
  41. J Cell Mol Med. 2024 Dec;28(23): e70240
    Role of Autophagy in Type 2 Diabetes Mellitus: The Metabolic Clash.
    Yousef Abud Alanazi, Haydar M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Marios Papadakis, Mostafa M Bahaa, Walaa A Negm, Faisal Holil AlAnazi, Mohammed Alrouji, Gaber El-Saber Batiha.
      Type 2 diabetes mellitus (T2DM) is developed due to the development of insulin resistance (IR) and pancreatic β cell dysfunction with subsequent hyperglycaemia. Hyperglycaemia-induced oxidative stress and endoplasmic reticulum (ER) stress enhances inflammatory disorders, leading to further pancreatic β cell dysfunction. These changes trigger autophagy activation, which recycles cytoplasmic components and injured organelles. Autophagy regulates pancreatic β cell functions by different mechanisms. Though the exact role of autophagy in T2DM is not completely elucidated, that could be beneficial or detrimental. Therefore, this review aims to discuss the exact role of autophagy in the pathogenesis of T2DM.
    Keywords:  autophagy; pancreatic β cell; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1111/jcmm.70240
  42. Anal Chem. 2024 Dec 09.
    A Mitochondria-Targeting and Peroxynitrite-Activatable Ratiometric Fluorescent Probe for Precise Tracking of Oxidative Stress-Induced Mitophagy.
    Xianzhi Chai, Xiuhua Ma, Lu-Lu Sun, Yuqing Hu, Weijian Zhang, Shiyao Zhang, Jiaqi Zhou, Liangliang Zhu, Hai-Hao Han, Xiao-Peng He.
      Mitochondria are the energy factory of cells and can be easily damaged by reactive oxygen species (ROS) because of the frequent occurrence of oxidative stress. Abnormality in mitophagy is often associated with many diseases including inflammation, cancer, and aging. While previously developed fluorescent probes mainly focus on detecting just ROS or mitophagy, quite rare studies have endeavored to comprehensively capture the entire mitophagic process, encompassing both the production of ROS and the induction of mitophagy. Herein, we report a new ratiometric fluorescent probe NA-DP for tracking peroxynitrite (ONOO-) as well as the subsequent oxidative stress-induced mitophagy. To a naphthalimide-based dye, an ONOO--responsive diphenyl phosphinate moiety and the mitochondria-targeting triphenylphosphonium group were attached. The probe showed a highly selective response to ONOO- through an addition-elimination reaction with diphenyl phosphinate. Owing to its outstanding pH stability and organelle-targeting ability, NA-DP was successfully used to detect mitophagy induced by oxidative stress after the generation of ONOO-. In the meantime, the probe was also used to track starvation-induced mitophagy and indicate that starvation-induced mitophagy is independent of ONOO-. Therefore, NA-DP has the ability to precisely track oxidative stress-induced mitophagy by distinguishing it from starvation-induced mitophagy. This study offers a new chemical tool to study the relationship between ROS generation and mitophagy.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03759
  43. Dermatol Pract Concept. 2024 Oct 30. 14(4):
    mTORC1 and mTORC2 Levels in Patients with Psoriasis.
    İlayda Esna Gülsunay, İlknur Altunay, Tuğba Kum, Aslı Aksu Çerman.
       INTRODUCTION: In recent years, there has been a growing emphasis on the role of the mammalian target of rapamycin (mTOR) pathway in the pathogenesis of psoriasis. This intracellular signaling pathway is known as the main control pathway of metabolism and is of particular interest in this context.
    OBJECTIVES: To investigate the importance of the mTOR pathway in the pathogenesis of plaque psoriasis.
    METHODS: A total of forty patients with plaque psoriasis and 40 non-psoriatic volunteers were included in this case-control study. The fasting serum levels of mTORC1 and mTORC2 in the study groups were examined by enzyme-linked immunosorbent assay.
    RESULTS: Serum levels of both mTORC1 and mTORC2 were found to be significantly lower in patients with plaque psoriasis than in controls (P = 0.001). A positive correlation was identified between serum mTORC1 and serum mTORC2 levels in patients with plaque psoriasis (p=0.001, r=0.826).
    CONCLUSION: The lower serum levels of mTORC1 and mTORC2 complexes, which are active signaling molecules in the cell, were observed in patients with plaque psoriasis. This suggests that these levels may serve as an indicator of increased intracellular activation of these molecules. It is our opinion that agents that can effectively inhibit both mTOR complexes may be more effective in the treatment of psoriasis.
    DOI:  https://doi.org/10.5826/dpc.1404a266
  44. J Insect Physiol. 2024 Dec 09. pii: S0022-1910(24)00129-X. [Epub ahead of print]161 104741
    Autophagy in the retina affects photoreceptor synaptic plasticity and behavior.
    Aleksandra Tyszka, Kornel Szypulski, Elzbieta Pyza, Milena Damulewicz.
      The visual system is a sensory system which is sensitive to light and detects photic stimuli. It plays many important functions, such as vision, circadian clock entrainment and regulation of sleep-wake behavior. The interconnection between the visual system and clock network is precisely regulated. The outer layer of the visual system called the retina, is composed of opsin-based photoreceptors that, in addition to visual information, provide photic information for the circadian clock, which in turn, regulates daily rhythms, such as activity and sleep patterns. The retina houses its own circadian oscillators (belonging to peripheral oscillators), however, they are also controlled by the main clock (pacemaker). Photoreceptor cells show many clock and light-dependent rhythms, such as the rhythms in synaptic plasticity or rhodopsin turnover, but their precise regulation is still not completely understood. In this study, we provided evidence that one of the mechanisms involved in the regulation of retinal rhythms is autophagy. We showed that autophagy is rhythmic in photoreceptors, with a specific daily pattern of autophagosome levels in different cells. Moreover, our data suggest that rhythmic autophagy-dependent degradation of the presynaptic protein Bruchpilot or photosensitive rhodopsin is involved in the regulation of daily rhythms observed in the retina. In effect, autophagy disruption in the photoreceptors, which affects photic signal transmission to the main clock neurons, causes changes in sleep level and pattern.
    Keywords:  Biological clock; Bruchpilot; Drosophila melanogaster; Sleep; Vision
    DOI:  https://doi.org/10.1016/j.jinsphys.2024.104741
  45. Redox Biol. 2024 Dec 05. pii: S2213-2317(24)00434-8. [Epub ahead of print]79 103456
    Hydrogen sulfide attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB-mediated autophagic flux.
    Xia Wang, Xiying Huang, Yongya Zhang, Huanhuan Huo, Guo Zhou, Linghong Shen, Long Li, Ben He.
      Disturbed flow (DF) plays a critical role in the development and progression of cardiovascular disease (CVD). Hydrogen sulfide (H2S) is involved in physiological processes within the cardiovascular system. However, its specific contribution to DF-induced vascular remodeling remains unclear. Here, we showed that the H2S donor, NaHS suppressed DF-induced vascular remodeling in mice. Further experiments demonstrated that NaHS inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF), as well as the autophagy triggered by DF and PDGF. Mechanistically, RNA-Seq results revealed that NaHS counteracted the PDGF-induced upregulation of lactate dehydrogenase B (LDHB). Overexpression of LDHB abolished the protective effect of NaHS on DF-induced vascular remodeling. Furthermore, LDHB interacted with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), leading to lysosomal acidification, a process that was attenuated by NaHS treatment. The residues of leucine (Leu) 57 in ATP6V1A and serine (Ser) 269 in LDHB are critical for their interaction. Notably, the expression of LDHB was found to be elevated in vascular tissues from patients with abdominal aortic aneurysms (AAA) and thoracic aortic aneurysms (TAA). These data identify a molecular mechanism by which H2S attenuates DF-induced vascular remodeling by inhibiting LDHB and disrupting the interaction between LDHB and ATP6V1A, thereby impeding the autophagy process. Our findings provide insight that H2S or targeting LDHB has therapeutic potential for preventing and treating vascular remodeling.
    Keywords:  Autophagy; Disturbed flow; Hydrogen sulfide; Lactate dehydrogenase B; Vacuolar-type proton ATPase catalytic subunit A
    DOI:  https://doi.org/10.1016/j.redox.2024.103456
  46. Adv Sci (Weinh). 2024 Dec 12. e2412205
    Ubiquitination of CD47 Regulates Innate Anti-Tumor Immune Response.
    Qian Gou, Bingjun Yan, Yalan Duan, Yilei Guo, Jing Qian, Juanjuan Shi, Yongzhong Hou.
      In addition to adaptive immune checkpoint of PD-1/PD-L1, the innate immune checkpoint SIRPα/CD47 plays an important role in regulation of tumor immune escape. However, the mechanism of CD47 ubiquitination on tumor immune escape remains unclear. Here it is found that TRAF2 bound to the C-terminal of CD47 cytoplasmic fragment and induced its ubiquitination, leading to inhibition of CD47 autophagic degradation by disrupting its binding to LC3, which in turn inhibited macrophage phagocytosis and promoted tumor immune escape. In contrast, loss of TRAF2 facilitated CD47 autophagic degradation and inhibited tumor immune escape. Moreover, autophagy induction promoted CD47 degradation and enhanced the efficacy of CD47 antibody anti-tumor immunotherapy. These findings revealed a novel mechanism of ubiquitination of CD47 on tumor immune escape.
    Keywords:  CD47; TRAF2; autophagy; immune escape; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202412205
  47. bioRxiv. 2024 Nov 26. pii: 2024.11.24.624947. [Epub ahead of print]
    Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
    David R Rawnsley, Moydul Islam, Chen Zhao, Yasaman Kargar Gaz Kooh, Adelita Mendoza, Honora Navid, Minu Kumari, Xumin Guan, John T Murphy, Jess Nigro, Attila Kovacs, Kartik Mani, Nathaniel Huebsch, Xiucui Ma, Abhinav Diwan.
       Background: Protein quality control (PQC) is critical for maintaining sarcomere structure and function in cardiac myocytes, and mutations in PQC pathway proteins, such as CRYAB (arginine to glycine at position 120, R120G) and BAG3 (proline to lysine at position 209, P209L) induce protein aggregate pathology with cardiomyopathy in humans. Novel observations in yeast and mammalian cells demonstrate mitochondrial uptake of cytosolic protein aggregates. We hypothesized that mitochondrial uptake of cytosolic protein aggregates and their removal by mitophagy, a lysosomal degradative pathway essential for myocardial homeostasis, facilitates cytosolic protein quality control in cardiac myocytes.
    Methods: Mice with inducible cardiac myocyte specific ablation of TRAF2 (TRAF2icKO), which impairs mitophagy, were assessed for protein aggregates with biochemical fractionation and super-resolution imaging in comparison to floxed controls. Induced pluripotent stem cell (iPSC)-derived cardiac myocytes with R120G knock-in to the CRYAB locus were assessed for localization of the CRYAB protein. Transgenic mice expressing R120G CRYAB protein (R120G-TG) were subjected to both TRAF2 gain-of-function (with AAV9-cardiac Troponin T promoter-driven TRAF2 transduction) and TRAF2 loss-of-function (with tamoxifen-inducible ablation of one Traf2 allele) in cardiac myocytes to determine the effect of mitophagy modulation on cardiac structure, function, and protein aggregate pathology.
    Results: Cardiomyocyte-specific ablation of TRAF2 results accumulation of mitochondrial and cytosolic protein aggregates and DESMIN mis-localization to protein aggregates. Isolated mitochondria take up cardiomyopathy-associated aggregate-prone cytosolic chaperone proteins, namely arginine to glycine (R120G) CRYAB mutant and proline to lysine (P209L) BAG3 mutant. R120G-CRYAB mutant protein increasingly localizes to mitochondria in human and mouse cardiomyocytes. R120G-TG mice demonstrate upregulation of TRAF2 in the mitochondrial fraction with increased mitophagy as compared with wild type. Adult-onset inducible haplo-insufficiency of TRAF2 resulted in accelerated mortality, impaired left ventricular systolic function and increased protein aggregates in R120G-TG mice as compared with controls. Conversely, AAV9-mediated TRAF2 transduction in R120G-TG mice reduced mortality and attenuated left ventricular systolic dysfunction, with reduced protein aggregates and restoration of normal localization of DESMIN, a cytosolic scaffolding protein chaperoned by CRYAB, as compared with control AAV9-GFP group.
    Conclusions: TRAF2-mediated mitophagy in cardiac myocytes facilitates removal of cytosolic protein aggregates and can be stimulated to ameliorate proteotoxic cardiomyopathy.
    DOI:  https://doi.org/10.1101/2024.11.24.624947
  48. Elife. 2024 Dec 09. pii: RP88916. [Epub ahead of print]12
    Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos.
    Marius Regin, Yingnan Lei, Edouard Couvreu De Deckersberg, Charlotte Janssens, Anfien Huyghebaert, Yves Guns, Pieter Verdyck, Greta Verheyen, Hilde Van de Velde, Karen Sermon, Claudia Spits.
      About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. Here, we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed activated p53 pathway and apoptosis proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signaling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to the removal of aneuploid cells from mosaic embryos.
    Keywords:  Embryology; apoptosis; autophagy; chromosomal mosaicism; chromosomes; developmental biology; gene expression; human; p53; proteotoxic stress
    DOI:  https://doi.org/10.7554/eLife.88916
  49. J Cell Mol Med. 2024 Dec;28(23): e70276
    TLR3 Knockdown Attenuates Pressure-Induced Neuronal Damage In Vitro.
    Li Lin, Zhongzhong Lv, Chao Zhou, Taiyang Zhu, Yuting Hu, Xiaoyu Sun, Hui Zhou, Miao Wang, Yongtao Lin, Guoqing Gu, Shang Wang, Yan Zhou, Jingjing Han, Guoliang Jin, Fang Hua.
      The disruption of nerve parenchyma and axonal networks triggered by spinal cord injury (SCI) can initiate a cascade of events associated with secondary injury. Toll-like receptors play a critical role in initiating and regulating immune-inflammatory responses following SCI; however, the precise involvement of Toll-like receptor-3 (TLR3) in secondary neuronal injury remains incompletely understood. To investigate the potential contribution of TLR3 in mediating neuronal pressure-induced damage, we established a stress-induced neuronal damage model using rat anterior horn motor neuron line (VSC4.1), which was subjected to varying levels and durations of sustained pressure. Our findings suggest that pressure induces neuronal damage and apoptosis, and reduced proliferation rates in VSC4.1 cells. Furthermore, this pressure-induced neuronal injury is accompanied by upregulation of TLR3 expression and activation of downstream TLR3 signalling molecules. Knockdown experiments targeting TLR3 significantly alleviate pressure-induced motor neuron injury and apoptosis within the anterior horn region while promoting mitochondria-related autophagy and reducing mitochondrial dysfunction via the TLR3/IRF3 and TLR3/NF-κB pathways.
    Keywords:  TLR3; apoptosis; autophagy; microtubule‐associated protein‐2; mitochondria; pressure‐injured; spinal cord injury
    DOI:  https://doi.org/10.1111/jcmm.70276
  50. Aging Cell. 2024 Dec 12. e14447
    Organellar quality control crosstalk in aging-related disease: Innovation to pave the way.
    Yu Li, Jinxin Qi, Linhong Guo, Xian Jiang, Gu He.
      Organellar homeostasis and crosstalks within a cell have emerged as essential regulatory and determining factors for the survival and functions of cells. In response to various stimuli, cells can activate the organellar quality control systems (QCS) to maintain homeostasis. Numerous studies have demonstrated that dysfunction of QCS can lead to various aging-related diseases such as neurodegenerative, pulmonary, cardiometabolic diseases and cancers. However, the interplay between QCS and their potential role in these diseases are poorly understood. In this review, we present an overview of the current findings of QCS and their crosstalk, encompassing mitochondria, endoplasmic reticulum, Golgi apparatus, ribosomes, peroxisomes, lipid droplets, and lysosomes as well as the aberrant interplays among these organelles that contributes to the onset and progression of aging-related disorders. Furthermore, potential therapeutic approaches based on these quality control interactions are discussed. Our perspectives can enhance insights into the regulatory networks underlying QCS and the pathology of aging and aging-related diseases, which may pave the way for the development of novel therapeutic targets.
    Keywords:  aging‐related diseases; cellular organelle; crosstalk; quality control
    DOI:  https://doi.org/10.1111/acel.14447
  51. Neurochem Res. 2024 Dec 09. 50(1): 53
    Physiological and Pathological Role of mTOR Signaling in Astrocytes.
    Luise Hochmuth, Johannes Hirrlinger.
      The mammalian target of rapamycin (mTOR) signaling pathway is one of the key regulators of cellular energy metabolism. It senses diverse alterations in the extracellular environment such as availability of nutrients and growth factors, and mediates the corresponding intracellular response. In the brain, astrocytes crucially contribute to energy and neurotransmitter metabolism, and numerous other functions. However, the relevance of physiological, astrocytic mTOR signaling in maintaining brain homeostasis and function is not well understood. Pathophysiological mTOR signaling is involved in manifold diseases in the central nervous system and most of the knowledge about astrocytic mTOR signaling has been derived from observations on these disorders. Dysregulation of the mTOR signaling pathway impairs important functions of astrocytes including neurotransmitter uptake and -signaling as well as energy metabolism. Some of these alterations could trigger neuropathological conditions such as epilepsy. This review focuses on how mTOR signaling regulates properties of astrocytes, and how these signaling events might contribute to the physiological function of the brain.
    Keywords:  Astrocyte; Glutamate; Mitochondria; mTOR
    DOI:  https://doi.org/10.1007/s11064-024-04306-6
  52. Theranostics. 2024 ;14(19): 7333-7348
    Branched-chain amino acids deficiency promotes diabetic cardiomyopathy by activating autophagy of cardiac fibroblasts.
    Ze-Yu Zhou, Kai Song, Zhi-Yan Liu, Yu-Fan Ke, Yan Shi, Ke Cai, Rui Zhao, Xin Sun, Hui Tao, Jian-Yuan Zhao.
      Rationale: More than half of the patients with type II diabetes mellitus (T2D) develop diabetic cardiomyopathy (DCM). Glycemic control alone cannot effectively prevent or alleviate DCM. Methods: Herein, we concentrated on the variations in levels of metabolites between DCM and T2D patients without cardiomyopathy phenotype. In high-fat diet/low-dose streptozotocin-induced T2D and leptin receptor-deficient diabetic mouse models, we investigated the effect of altering branched-chain amino acids (BCAAs) levels on DCM. Results: We discovered that the levels of plasma BCAAs are notably lower in 15 DCM patients compared to 19 T2D patients who do not exhibit cardiomyopathy phenotype, using nuclear magnetic resonance analysis. This finding was further validated in two additional batches of samples, 123 DCM patients and 129 T2D patients based on the BCAA assay kit, and 30 DCM patients and 30 T2D patients based on the LC-MS/MS method, respectively. Moreover, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated cardiomyopathy phenotypes in diabetic mice. Furthermore, BCAA deficiency promoted cardiac fibroblast activation by stimulating autophagy in DCM mice. Mechanistically, BCAA deficiency activated autophagy via the AMPK-ULK1 signaling pathway in cardiac fibroblasts. Using pharmacological approaches, we validated our findings that autophagy inhibition relieved, whereas autophagy activation aggravated, DCM phenotypes. Conclusions: Taken together, we describe a novel perspective wherein BCAA supplementation may serve as a potential therapeutic agent to mitigate DCM and fibrosis. Our findings provide insights for the development of preventive measures for DCM.
    Keywords:  Autophagy; Branched-chain amino acid; Cardiac fibroblasts; Cardiac fibrosis; Diabetic cardiomyopathy
    DOI:  https://doi.org/10.7150/thno.102708
  53. Autophagy. 2024 Dec 11.
    Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of cushing syndrome.
    Hui Pan, Ai-Ling Tian, Fréderic Castinetti, Isabelle Martins, Oliver Kepp, Guido Kroemer.
      DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed "Cushing syndrome", which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of Dbi/Acbp in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations.
    Keywords:  Disease model; monoclonal antibody; resmetirom; stress; “iatrogenic cushing’s syndrome”
    DOI:  https://doi.org/10.1080/15548627.2024.2437649
  54. J Adv Res. 2024 Dec 10. pii: S2090-1232(24)00591-5. [Epub ahead of print]
    ORP5 promotes cardiac hypertrophy by regulating the activation of mTORC1 on lysosome.
    Di Zhao, Ran Xu, Yufei Zhou, Jiaying Wu, Xiaoxue Zhang, Hong Lin, Jienan Wang, Zhiwen Ding, Yunzeng Zou.
       INTRODUCTION: Oxysterol binding protein (OSBP)-related protein 5 (ORP5) mainly functions as a lipid transfer protein at membrane contact sites (MCS). ORP5 facilitates cell proliferation through the activation of mTORC1 signaling. While the pro-hypertrophic effects of mTORC1 are well-documented, the specific role of ORP5 in the context of pathological cardiac hypertrophy remains inadequately understood.
    METHODS: To investigate the role of ORP5 in pathological cardiac hypertrophy, AAV9-treated mice and neonatal rat ventricular myocytes (NRVMs) were utilized. Cardiac function, morphology, and mTORC1 signaling alterations induced by pro-hypertrophic stimuli were assessed in both myocardium and NRVMs. Additionally, a range of molecular techniques were employed to elucidate the regulatory mechanisms of ORP5 on mTORC1 in hypertrophied hearts.
    RESULTS: Increased expression of ORP5 was observed in the hearts of patients with hypertrophic cardiomyopathy (HCM), in mice subjected to transverse aortic constriction (TAC), and in NRVMs treated with angiotensin II (AngII). We found that ORP5 binds to mTOR in cardiomyocytes. Upon exposure to TAC surgery, ORP5-deficient hearts exhibited enhanced cardiac function, reduced cardiomyocyte hypertrophy, and diminished collagen deposition than wild type. Conversely, overexpression of ORP5 significantly aggravated hypertrophic responses in both hearts and NRVMs. Notably, the promotion of cardiac hypertrophy induced by ORP5 overexpression was reversed by rapamycin, an inhibitor of mTORC1. Mechanistically, our study elucidated that the ORD domain of ORP5 interacts with mTORC1, facilitating its translocation to the outer membrane of the lysosome for subsequent activation. This activation triggers the downstream signaling pathways involving S6K1 and 4E-BP1, which initiate protein synthesis, thereby promoting pathological cardiac hypertrophy.
    CONCLUSIONS: Our findings provide the inaugural evidence that ORP5 facilitates pathological ventricular hypertrophy through the translocation of mTORC1 to the lysosome for subsequent activation. Consequently, ORP5 has the potential to serve as a diagnostic biomarker or therapeutic target for pathological cardiac hypertrophy in the future.
    Keywords:  Heart failure; Lysosome; ORP5; Pathological cardiac hypertrophy; mTORC1
    DOI:  https://doi.org/10.1016/j.jare.2024.12.014
  55. Trends Mol Med. 2024 Dec 12. pii: S1471-4914(24)00313-7. [Epub ahead of print]
    Treating Niemann-Pick C lysosomal storage: approved and emerging approaches.
    Andrés D Klein, Emily R Eden, Silvana Zanlungo.
      
    Keywords:  Niemann-Pick type C; lysosomal storage disorders; neurodegeneration; rare disease; therapeutics
    DOI:  https://doi.org/10.1016/j.molmed.2024.11.011
  56. Aging Dis. 2024 Dec 03.
    Role of AMPK and Sirtuins in Aging Heart: Basic and Translational Aspects.
    Maria Luisa Barcena, Muhammad Aslam, Kristina Norman, Christiane Ott, Yury Ladilov.
      Aging is a key risk factor for numerous diseases, including cardiac diseases. High energy demands of the heart require precise cellular energy sensing to prevent metabolic stress. AMPK and sirtuins are key intracellular metabolic sensors regulating numerous cell functions, like mitochondrial function and biogenesis, autophagy, and redox balance. However, their function is impaired during the aging process leading to mitochondrial dysfunction, oxidative stress, and inflammation culminating in cardiovascular diseases. The underlying molecular mechanisms leading to dysfunction of metabolic sensing in the aging heart are complex and comprise both intracellular and systemic age-related alterations. In this study, we overview the current knowledge on the impact of aging on cardiac metabolic sensing, with a focus on AMPK and sirtuins, while mTOR pathway was only marginally considered. A particular focus was given to systemic factors, e.g., inflammation, vascular diseases, and microbiome.
    DOI:  https://doi.org/10.14336/AD.2024.1216
  57. Brain Res. 2024 Dec 10. pii: S0006-8993(24)00653-X. [Epub ahead of print]1850 149398
    Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.
    Dandan Chen, Yuan Guo, Meng Zhang, Xingran Liu, Baowen Zhang, Xianjuan Kou.
      Notch signaling, a classical signaling pathway of neurogenesis, is downregulated during the aging and age-related neurodegenerative diseases. Exercise has been proposed as an effective lifestyle intervention for delaying cognitive decline. However, it remains unclear whether exercise intervention could alleviate cognitive decline by modulating neurogenesis in naturally aging rats. In this study, 21-month-old natural aging rats were used to study brain aging. The natural aging rats underwent different forms of exercise training (aerobic exercise or strength training or comprehensive exercise with aerobic exercise and strength training) for 12 consecutive weeks. The cognitive function of natural aging rats was determined by Morris Water Maze. Notch signaling, autophagy-related proteins and hippocampal neurogenesis were examined by immunofluorescence, qRT-PCR and Western blot. Results showed that natural aging rats exhibited cognitive decline, accumulation of AD pathological proteins (APP and Aβ), and decreased neurogenesis (decreased DCX, Ki67 and GFAP), compared with the young control rats. Moreover, a significant decline in Notch signaling and autophagy was found in the hippocampus of natural aging rats. However, different forms of exercise upregulated Notch signaling and its downstream target genes, as well as autophagy-related proteins, including LC3, Beclin1, and p62. In summary, our data suggest that different forms of exercise can mitigate brain aging by upregulating Notch signaling and autophagy, thereby increasing hippocampal neurogenesis and improves spatial learning and memory abilities.
    Keywords:  Autophagy; Cognitive dysfunction; Exercise intervention; Notch signaling
    DOI:  https://doi.org/10.1016/j.brainres.2024.149398
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