bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024‒11‒17
fifty-six papers selected by
Viktor Korolchuk, Newcastle University
  1. Prolonged glutamine starvation reactivates mTOR to inhibit autophagy and initiate autophagic lysosome reformation to maintain cell viability.
  2. Opposing roles for AMPK in regulating distinct mitophagy pathways.
  3. Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential.
  4. PKA Regulates Autophagy Through Lipolysis During Fasting.
  5. A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
  6. Unveiling GATOR2 Function: Novel Insights from Drosophila Research.
  7. The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.
  8. VPS4A is the selective receptor for lipophagy in mice and humans.
  9. Regulation of autophagy by Rab27B in colorectal cancer.
  10. An updated outlook on autophagy mechanism and how it supports acute myeloid leukemia maintenance.
  11. Bound by the love for cholesterol: A transporter meets a GPCR.
  12. Autophagy-lysosomal pathway impairment and cathepsin dysregulation in Alzheimer's disease.
  13. ULK1 as a therapeutic target in kidney diseases: Current perspective.
  14. Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27.
  15. SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD.
  16. Neuregulin 4 attenuates pancreatic β-cell apoptosis induced by lipotoxicity via activating mTOR-mediated autophagy.
  17. Autophagosome development and chloroplast segmentation occur synchronously for piecemeal degradation of chloroplasts.
  18. The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells.
  19. Autophagy and proteasomes in thymic epithelial cells: essential bulk protein degradation systems for immune homeostasis maintenance.
  20. Overexpression of TECPR1 improved cognitive function of P301S-tau mice via activation of autophagy in the early and late process.
  21. Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis.
  22. The role of autophagy in brain health and disease: Insights into exosome and autophagy interactions.
  23. Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
  24. Morphological analysis of autophagy in axonal degeneration in gracile axonal dystrophy mice.
  25. Enhanced Gαq Signaling in TSC2-deficient Cells Is Required for Their Neoplastic Behavior.
  26. Calcium signaling from damaged lysosomes induces cytoprotective stress granules.
  27. High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias.
  28. IL-32γ Induced Autophagy Through Suppression of MET and mTOR Pathways in Liver Tumor Growth Inhibition.
  29. TPC1 regulates melanoma tumourigenesis via mTORC1 and TFEB.
  30. NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy.
  31. Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway.
  32. Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.
  33. Activation of the mTOR pathway enhances PPARγ/SREBP-mediated lipid synthesis in human meibomian gland epithelial cells.
  34. TFEB links the cGAS-STING pathway to lysosome biogenesis.
  35. Stenosing Crohn's disease patients display gut autophagy/oxidative stress imbalance.
  36. STING orchestrates microglia polarization via interaction with LC3 in autophagy after ischemia.
  37. Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.
  38. MTOR maintains endothelial cell integrity to limit lung vascular injury.
  39. Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy.
  40. Atg2 controls Drosophila hematopoiesis through the PVR/TOR signaling pathways.
  41. Avian TRIM13 attenuates antiviral innate immunity by targeting MAVS for autophagic degradation.
  42. PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
  43. Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance.
  44. Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy.
  45. Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.
  46. HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
  47. αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury.
  48. Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster.
  49. The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce RNH1/miR-99a/mTOR-Mediated Autophagy and Apoptosis.
  50. Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
  51. RNF13 protects neurons against ischemia-reperfusion injury via stabilizing p62-mediated Nrf2/HO-1 signaling pathway.
  52. RTA408 alleviates retinal ganglion cells damage in mouse glaucoma by inhibiting excessive autophagy.
  53. TSPO Exacerbates Sepsis-Induced Cardiac Dysfunction by Inhibiting p62-Mediated Autophagic Flux via the ROS-RIP1/RIP3-Exosome Axis.
  54. Dendrobium nobile Lindl. alkaloids protect CCl4-induced acute liver injury via upregulating LAMP1 expression and activating autophagy flux.
  55. Ally or traitor: the dual role of p62 in caspase-2 regulation.
  56. Amantadine against glioma via ROS-mediated apoptosis and autophagy arrest.
  1. Int J Biochem Cell Biol. 2024 Nov 13. pii: S1357-2725(24)00187-0. [Epub ahead of print] 106694
    Prolonged glutamine starvation reactivates mTOR to inhibit autophagy and initiate autophagic lysosome reformation to maintain cell viability.
    Amruta Singh, Kewal Kumar Mahapatra, Prakash Priyadarshi Praharaj, Srimanta Patra, Soumya Ranjan Mishra, Sankargouda Patil, Sujit Kumar Bhutia.
      Autophagy, a cellular recycling mechanism, utilizes lysosomes for cellular degradation. Prolonged autophagy reduces the pool of functional lysosomes in the cell. However, lysosomal homeostasis is maintained through the regeneration of functional lysosomes during the terminal stage of autophagy, i.e. Autophagic lysosome reformation (ALR). Through confocal microscopy during glutamine starvation, we unravel the regeneration of tubules from autolysosomes by undertaking significant membrane remodeling, which majorly depends on mTOR reactivation, RAB7 dissociation, phosphatidyl inositol 3 phosphate (PI3P) dependent dynamin 2 and clathrin recruitment. In glutamine-starved cells, we found mTOR is the central modulator in regulating ALR initiation, and its pharmacological inhibition with rapamycin leads to a decrease in lysosomal tubulation. Moreover, RAB7 and Clathrin are essential for tubule elongation and it showed that siRNA targeting RAB7 and Clathrin restricts tubule initiation under glutamine starvation. In this setting, we examined the physiological relevance of ALR during prolonged glutamine deprivation and found that genetic and pharmacological inhibition of critical proteins involved in ALR promotes cell death in oral cancer cells, establishing ALR is essential for maintaining cell survival during stress.
    Keywords:  Autolysosome; Autophagic lysosome reformation; Autophagy; Mammalian target of Rapamycin; Proto-lysosome
    DOI:  https://doi.org/10.1016/j.biocel.2024.106694
  2. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]
    Opposing roles for AMPK in regulating distinct mitophagy pathways.
    Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.
      Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
    Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
  3. Acta Pharmacol Sin. 2024 Nov 15.
    Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential.
    Jin Wu, Wan Xu, Ying Su, Guang-Hui Wang, Jing-Jing Ma.
      The pathological hallmarks of various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease prominently feature the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA) has emerged as a distinct autophagic process that coordinates the lysosomal degradation of specific proteins bearing the pentapeptide motif Lys-Phe-Glu-Arg-Gln (KFERQ), a recognition target for the cytosolic chaperone HSC70. Beyond its role in protein quality control, recent research underscores the intimate interplay between CMA and immune regulation in neurodegeneration. In this review, we illuminate the molecular mechanisms and regulatory pathways governing CMA. We further discuss the potential roles of CMA in maintaining neuronal proteostasis and modulating neuroinflammation mediated by glial cells. Finally, we summarize the recent advancements in CMA modulators, emphasizing the significance of activating CMA for the therapeutic intervention in neurodegenerative diseases.
    Keywords:  CMA modulators; chaperone-mediated autophagy; neurodegenerative diseases; neuroinflammation; neuronal proteostasis
    DOI:  https://doi.org/10.1038/s41401-024-01416-3
  4. Mol Cells. 2024 Nov 13. pii: S1016-8478(24)00174-2. [Epub ahead of print] 100149
    PKA Regulates Autophagy Through Lipolysis During Fasting.
    Yul Ji, Yong Geun Jeon, Won Taek Lee, Ji Seul Han, Kyung Cheul Shin, Jin Young Huh, Jae Bum Kim.
      Autophagy is a crucial intracellular degradation process that provides energy and supports nutrient deprivation adaptation. However, the mechanisms by which these cells detect lipid scarcity and regulate autophagy are poorly understood. In this study, we demonstrate that protein kinase A (PKA)-dependent lipolysis delays autophagy initiation during short-term nutrient deprivation by inhibiting AMP-activated protein kinase (AMPK). Using coherent anti-Stokes Raman spectroscopy, we visualized free fatty acids (FFAs) in vivo and observed that lipolysis-derived FFAs were used before the onset of autophagy. Our data suggest that autophagy is triggered when the supply of FFAs is insufficient to meet energy demands. Furthermore, PKA activation promotes lipolysis and suppresses AMPK-driven autophagy during early fasting. Disruption of this regulatory axis impairs motility and reduces the lifespan of Caenorhabditis elegans during fasting. These findings establish PKA as a critical regulator of catabolic pathways, prioritizing lipolysis over autophagy by modulating AMPK activity to prevent premature autophagic degradation during transient nutrient deprivation.
    Keywords:  AMP-activated protein kinase; Autophagy; Caenorhabditis elegans; Free fatty acid; Lipolysis; Protein kinase A
    DOI:  https://doi.org/10.1016/j.mocell.2024.100149
  5. Autophagy. 2024 Nov 09.
    A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
    Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su.
      PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of Rnf7 in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.
    Keywords:  Heart failure; RBX2/SAG; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2423329
  6. Cells. 2024 Oct 30. pii: 1795. [Epub ahead of print]13(21):
    Unveiling GATOR2 Function: Novel Insights from Drosophila Research.
    Lucia Bettedi, Yingbiao Zhang, Shu Yang, Mary A Lilly.
      The multiprotein Target of Rapamycin (TOR) Complex 1 (TORC1) is a serine/threonine kinase that stimulates anabolic metabolism and suppresses catabolism. Deregulation of TORC1 is implicated in various human pathologies, including cancer, epilepsy, and neurodegenerative disorders. The Gap Activity Towards Rags (GATOR) complex contains two subcomplexes: GATOR1, which inhibits TORC1 activity; and GATOR2, which counteracts GATOR1s function. Structural and biochemical studies have elucidated how GATOR1 regulates TORC1 activity by acting as a GTPase activating protein for Rag GTPase. However, while cryogenic electron microscopy has determined that the structure of the multi-protein GATOR2 complex is conserved from yeast to humans, how GATOR2 inhibits GATOR1 remains unclear. Here, we describe recent whole-animal studies in Drosophila that have yielded novel insights into GATOR2 function, including identifying a novel role for the GATOR2 subunit WDR59, redefining the core proteins sufficient for GATOR2 activity, and defining a TORC1-independent role for GATOR2 in the regulation of the lysosomal autophagic endomembrane system. Additionally, the recent characterization of a novel methionine receptor in Drosophila that acts through the GATOR2 complex suggests an attractive model for the evolution of species-specific nutrient sensors. Research on GATOR2 function in Drosophila highlights how whole-animal genetic models can be used to dissect intracellular signaling pathways to identify tissue-specific functions and functional redundancies that may be missed in studies confined to rapidly proliferating cell lines.
    Keywords:  Drosophila; GATOR1; GATOR2; MIT/TFE; Rag GTPase; TORC1; UNMET; Wdr59; species-specific nutrient sensor
    DOI:  https://doi.org/10.3390/cells13211795
  7. Cell Mol Life Sci. 2024 Nov 11. 81(1): 450
    The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.
    Elizabeth Vafiadaki, Evangelia G Kranias, Aristides G Eliopoulos, Despina Sanoudou.
      Phospholamban (PLN) plays a crucial role in regulating sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Mutations within the PLN gene have been detected in patients with cardiomyopathy, with the heterozygous variant c.40_42delAGA (p.R14del) of PLN being the most prevalent. Investigations into the mechanisms underlying the pathology of PLN-R14del have revealed that cardiac cells from affected patients exhibit pathological aggregates containing PLN. Herein, we performed comprehensive molecular and cellular analyses to delineate the molecular aberrations associated with the formation of these aggregates. We determined that PLN aggregates contain autophagic proteins, indicating inefficient degradation via the autophagy pathway. Our findings demonstrate that the expression of PLN-R14del results in diminished autophagic flux due to impaired fusion between autophagosomes and lysosomes. Mechanistically, this defect is linked to aberrant recruitment of key membrane fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+ homeostasis. Collectively, these results highlight a novel function of PLN-R14del in regulating autophagy, that may contribute to the formation of pathogenic aggregates in patients with cardiomyopathy. Prospective strategies tailored to ameliorate impaired autophagy may hold promise against PLN-R14del disease.
    Keywords:  Aggregates; Autophagy; Cardiomyopathy; Precision medicine
    DOI:  https://doi.org/10.1007/s00018-024-05471-1
  8. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00862-1. [Epub ahead of print]
    VPS4A is the selective receptor for lipophagy in mice and humans.
    Debajyoti Das, Mridul Sharma, Deepanshi Gahlot, Shervin S Nia, Chandrima Gain, Matthew Mecklenburg, Z Hong Zhou, Mathieu Bourdenx, Lipi Thukral, Nuria Martinez-Lopez, Rajat Singh.
      Lipophagy is a ubiquitous mechanism for degradation of lipid droplets (LDs) in lysosomes. Autophagy receptors selectively target organelles for lysosomal degradation. The selective receptor for lipophagy remains elusive. Using mouse liver phosphoproteomics and human liver transcriptomics, we identify vacuolar-protein-sorting-associated protein 4A (VPS4A), a member of a large family AAA+ ATPases, as a selective receptor for lipophagy. We show that phosphorylation of VPS4A on Ser95,97 and its localization to LDs in response to fasting drives lipophagy. Imaging/three-dimensional (3D) reconstruction and biochemical analyses reveal the concomitant degradation of VPS4A and LDs in lysosomes in an autophagy-gene-7-sensitive manner. Either silencing VPS4A or targeting VPS4AS95,S97 phosphorylation or VPS4A binding to LDs or LC3 blocks lipophagy without affecting other forms of selective autophagy. Finally, VPS4A levels and markers of lipophagy are markedly reduced in human steatotic livers-revealing a fundamental role of VPS4A as the lipophagy receptor in mice and humans.
    Keywords:  MASLD; VPS4A; autophagy; human; lipid droplet; lipophagy; liver; lysosome; phosphorylation; receptor
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.022
  9. Int J Biochem Cell Biol. 2024 Nov 12. pii: S1357-2725(24)00186-9. [Epub ahead of print] 106693
    Regulation of autophagy by Rab27B in colorectal cancer.
    Sahida Afroz, Ranjan Preet, Vikalp Vishwakarma, Andrew E Evans, Alexa N Magstadt, Dan A Dixon.
      Autophagy is a cellular recycling process that is associated with tumor growth, anti-tumor immune responses, and therapy resistance in colorectal cancer (CRC). In this report, we identify the small GTPase Rab27B to control the autophagy process in CRC. Depletion of Rab27B showed an abnormal accumulation of autophagy vesicles and increased autophagy markers in CRC cells, indicating autophagy dysregulation. Image analysis indicated that autophagy flux is blocked at the autophagosome/lysosome fusion step when Rab27B is lost. While Rab27B deficient cells are proficient at growth under 2D in vitro conditions, cell growth was significantly impacted in both in vitro 3D growth and in vivo tumorigenesis studies. Together, these results demonstrate a new role of Rab27B in the autophagy trafficking process in CRC and identify Rab27B as a potential therapeutic target for CRC.
    Keywords:  Autophagy; Colorectal Cancer; Rab27B
    DOI:  https://doi.org/10.1016/j.biocel.2024.106693
  10. Biochim Biophys Acta Rev Cancer. 2024 Nov 06. pii: S0304-419X(24)00145-8. [Epub ahead of print]1879(6): 189214
    An updated outlook on autophagy mechanism and how it supports acute myeloid leukemia maintenance.
    Brunno Gilberto Santos de Macedo, Manuela Albuquerque de Melo, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto, Fabiola Traina.
      The gradual acquisition of genetic and epigenetic disturbances bestows malignant traits upon hematopoietic stem cells, subverting them into a founder and reservoir cell for de novo acute myeloid leukemia (AML) known as leukemic stem cells (LSC). Beyond its molecular heterogeneity, AML is also characterized by rewiring biological processes to support its onset and maintenance. LSC were observed to inherently and actively trigger mitochondrial turnover through selective autophagic removal such that impairing the process led to cell differentiation at the expense of its stemness. This review provides a current take on autophagy regulation mechanisms according to the current molecular characterization of the process; describes autophagy as a drug resistance mechanism, and a pivotal mechanism whereby LSC harmonize their strong reliance on mitochondrial respiration to obtain energy, and their necessity for lower internal oxidative stress to avoid exhaustion. Therefore, targeting autophagy presents a promising strategy to promote long-term remissions in AML.
    Keywords:  Acute myeloid leukemia; Autophagy; Leukemic stem cell; Mitophagy; Selective autophagy
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189214
  11. Cell. 2024 Nov 14. pii: S0092-8674(24)01215-7. [Epub ahead of print]187(23): 6518-6520
    Bound by the love for cholesterol: A transporter meets a GPCR.
    Divyanshu Tiwari, Nabarun Roy, Arun K Shukla.
      In a recently published article in Nature, Bayly-Jones et al. report the cryo-EM structures of a lysosomal cholesterol sensor, LYCHOS, also known as GPR155, which reveals a unique fusion of a plant auxin-transporter-like domain with a seven-transmembrane GPCR-like domain and elucidates mechanistic insights into cellular regulation of mTORC1 activity.
    DOI:  https://doi.org/10.1016/j.cell.2024.10.033
  12. Front Mol Biosci. 2024 ;11 1490275
    Autophagy-lysosomal pathway impairment and cathepsin dysregulation in Alzheimer's disease.
    Alquiandra Stefani Ferreira Mançano, Juliana Guanaes Pina, Bruna Rojas Froes, Juliana Mozer Sciani.
      Alzheimer's disease (AD) is characterized by neuronal loss, attributed to amyloid-beta (Aβ) aggregation and accumulation. The autophagy-lysosomal pathway, including cathepsins B and D, is crucial for protein degradation and clearance, but it is impaired in some diseases. This review summarizes current knowledge on the dysregulation of this pathway in AD. Accumulating evidence suggests that Aβ overload impairs autophagy-lysosomal function and cathepsin activity, exacerbating Aβ accumulation and neurodegeneration. However, the precise mechanisms underlying these interactions remain elusive. Despite these challenges, targeting the lysosomal pathway emerges as a promising therapeutic strategy, and a comprehensive understanding of the autophagy-lysosomal system is essential to develop effective interventions for AD.
    Keywords:  Alzheimer’s disease; autophagy; cathepsin B; cathepsin D; lysosome; β-amyloid
    DOI:  https://doi.org/10.3389/fmolb.2024.1490275
  13. Expert Opin Ther Targets. 2024 Nov 11. 1-12
    ULK1 as a therapeutic target in kidney diseases: Current perspective.
    Shruti Shreya, Neha Dagar, Vishwadeep Shelke, Bhupendra Puri, Anil Bhanudas Gaikwad.
      INTRODUCTION: Globally, ~850 million people are affected by different kidney diseases. The pathogenesis of kidney diseases is intricate, where autophagy is crucial for maintaining kidney homeostasis. Iteliminates damaged organelles, thus reducing renal lesions and allowing tissue regeneration. Therefore, targeting various autophagy proteins, e.g. Unc-51-like autophagy-activating kinase 1 (ULK1), is emerging as potential therapeutic strategy against kidney disease.AREAS COVERED: This review provides insights into the role of ULK1 as a therapeutic target in kidney diseases. Additionally, we have discussed the recent evidence based on pre-clinical studies for possible novel therapies modulating ULK1-mediated autophagy in kidney diseases.
    EXPERT OPINION: ULK1 is one of the critical regulators of autophagy. Moreover, ULK1 works differently for different types of kidney disease. Considering its significant role in kidney disease pathogenesis, it could be a potential target to tackle kidney diseases. However, the dynamic molecular understanding of ULK1 in the context of various kidney diseases is still in its infancy and should be investigated further.
    Keywords:  Autophagy; ULK1; kidney disease; kidney homeostasis; therapeutic target
    DOI:  https://doi.org/10.1080/14728222.2024.2421762
  14. Curr Biol. 2024 Nov 10. pii: S0960-9822(24)01457-X. [Epub ahead of print]
    Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27.
    Elizabeth R Gallagher, Peace T Oloko, Tessa C Fitch, Elizabeth M Brown, Lynn A Spruce, Erika L F Holzbaur.
      Maintenance of lysosomal integrity is essential for cell viability. Upon injury, lysosomes may be targeted for degradation via a selective form of autophagy known as lysophagy. The engulfment of a damaged lysosome by an autophagosome is mediated by the recruitment of adaptor proteins, including SQSTM1/p62. p62 promotes lysophagy via the formation of phase-separated condensates in a mechanism that is regulated by the heat shock protein HSP27. Here, we demonstrate a direct interaction between HSP27 and p62. We used structural modeling to predict the binding interface between HSP27 and p62 and identify several disease-associated mutations that map to this interface. We used proteomics to identify post-translational modifications of HSP27 that regulate HSP27 recruitment to stressed lysosomes, finding robust phosphorylation at several serine residues. Next, we characterized the upstream signaling mechanism leading to HSP27 phosphorylation and found that p38 mitogen-activated protein kinase (MAPK) and its effector kinase MAP kinase-activated protein kinase 2 (MK2) are activated upon lysosomal damage by the kinase mTOR and the production of intracellular reactive oxygen species (ROS). Increased ROS activates p38 MAPK, which in turn allows MK2-dependent phosphorylation of HSP27. Depletion of HSP27 or the inhibition of HSP27 phosphorylation alters the dynamics of p62 condensates on stressed lysosomes, significantly inhibiting p62-dependent lysophagy. Thus, we define a novel lysosomal quality control mechanism in which lysosomal injury triggers a p38 MAPK/MK2 signaling cascade promoting p62-dependent lysophagy. Further, this signaling cascade is activated by many cellular stressors, including oxidative and heat stress, suggesting that other forms of selective autophagy may be regulated by p38 MAPK/MK2/HSP27.
    Keywords:  HSP27; SQSTM1/p62; lysophagy; oligomers; p38 MAPK; phase separation; phosphorylation
    DOI:  https://doi.org/10.1016/j.cub.2024.10.061
  15. Mol Ther. 2024 Nov 09. pii: S1525-0016(24)00743-3. [Epub ahead of print]
    SNRK modulates mTOR-autophagy pathway for liver lipid homeostasis in MAFLD.
    Shan Lin, Xiusheng Qiu, Xiaoying Fu, Shuting Zhang, Changyong Tang, Jian Kuang, Haixia Guan, Shuiqing Lai.
      Metabolism-related fatty liver disease (MAFLD) is associated with abnormal fat accumulation in the liver. The exact mechanism underlying the occurrence and development of MAFLD remains to be elucidated. Here, we discovered that the expression of Sucrose non-fermenting-related kinase (SNRK) is elevated in the liver of the MAFLD population. Mice deficient in SNRK exhibited damage to fatty acid oxidation and persistent accumulation of lipids in the liver. Pharmacological inhibition of the mTOR pathway in SNRK-deficient mice restored autophagy and improved lipid accumulation. In terms of mechanism, we observed that SNRK binds to the raptor component of mTOR complex 1, promoting fatty acid oxidation in the liver by activating autophagy. Overexpression of SNRK in high-fat diet-induced obese mice restored autophagy and ameliorated lipid accumulation. Notably, we also demonstrated that overexpression of SNRK significantly enhanced fatty acid oxidation in the mouse liver. We further confirmed that SNRK is essential for the liver to regulate autophagy and fatty acid oxidation. These findings underscore the importance of SNRK's potential in the treatment of MAFLD.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.11.016
  16. Islets. 2024 Dec 31. 16(1): 2429854
    Neuregulin 4 attenuates pancreatic β-cell apoptosis induced by lipotoxicity via activating mTOR-mediated autophagy.
    Biao Zhu, Lei Sun, Junyao Tong, Yan Ding, Yanbo Shan, Mingjuan He, Xiaoyu Tian, Wen Mei, Lisheng Zhao, Ying Wang.
      Neuregulin 4 (Nrg4) is a brown fat-enriched endocrine factor that ameliorates lipid metabolism disorders. Autophagy is critical for pancreatic β-cell to counteract lipotoxicity-induced apoptosis. This study aimed at exploring whether Nrg4 attenuates lipotoxicity-induced β-cell apoptosis by regulating autophagy. The mouse pancreatic β-cell line MIN6 was cultured in palmitic acid (PA) with or without Nrg4 administration. Apoptosis rate, together with anti-apoptotic and pro-apoptotic protein levels, was investigated. Autophagic flux and autophagy-related protein levels along with related signaling pathways that regulate autophagy were also evaluated. Results showed that Nrg4 decreased PA-induced MIN6 apoptosis, enhanced anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) expression and reduced pro-apoptotic proteins Bcl-2-associated X protein (Bax) and cleaved-caspase 3 expressions. Autophagy levels in MIN6 also decreased with PA treatment and Nrg4 administration reactivated autophagy. Further, Nrg4 administration activated autophagy via the mammalian target of rapamycin (mTOR) signaling pathway. In addition, when the mTOR pathway was stimulated or autophagy was suppressed, the beneficial effects of Nrg4 administration on MIN6 apoptosis were diminished. These results imply that Nrg4 administration attenuates MIN6 apoptosis by promoting mTOR-dependent autophagy and thus may lead to a new therapeutic method for type 2 diabetes mellitus (T2DM).
    Keywords:  AMPK; apoptosis; autophagy; lipotoxicity; mTOR; neuregulin 4 (Nrg4)
    DOI:  https://doi.org/10.1080/19382014.2024.2429854
  17. Elife. 2024 Nov 07. pii: RP93232. [Epub ahead of print]12
    Autophagosome development and chloroplast segmentation occur synchronously for piecemeal degradation of chloroplasts.
    Masanori Izumi, Sakuya Nakamura, Kohei Otomo, Hiroyuki Ishida, Jun Hidema, Tomomi Nemoto, Shinya Hagihara.
      Plants distribute many nutrients to chloroplasts during leaf development and maturation. When leaves senesce or experience sugar starvation, the autophagy machinery degrades chloroplast proteins to facilitate efficient nutrient reuse. Here, we report on the intracellular dynamics of an autophagy pathway responsible for piecemeal degradation of chloroplast components. Through live-cell monitoring of chloroplast morphology, we observed the formation of chloroplast budding structures in sugar-starved leaves. These buds were then released and incorporated into the vacuolar lumen as an autophagic cargo termed a Rubisco-containing body. The budding structures did not accumulate in mutants of core autophagy machinery, suggesting that autophagosome creation is required for forming chloroplast buds. Simultaneous tracking of chloroplast morphology and autophagosome development revealed that the isolation membranes of autophagosomes interact closely with part of the chloroplast surface before forming chloroplast buds. Chloroplasts then protrude at the site associated with the isolation membranes, which divide synchronously with autophagosome maturation. This autophagy-related division does not require DYNAMIN-RELATED PROTEIN 5B, which constitutes the division ring for chloroplast proliferation in growing leaves. An unidentified division machinery may thus fragment chloroplasts for degradation in coordination with the development of the chloroplast-associated isolation membrane.
    Keywords:  A. thaliana; autophagy; cell biology; chloroplast; plant; plant biology
    DOI:  https://doi.org/10.7554/eLife.93232
  18. Bioorg Chem. 2024 Nov 03. pii: S0045-2068(24)00842-3. [Epub ahead of print]153 107937
    The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells.
    Xiaojie Liu, Yubin Jin, Mengli Zhang, Yanhe Jin, Jie Cao, Hangqi Dong, Xiangjing Fu, Cheng-Yun Jin.
      There has been growing interest in investigating anti-tumor drugs that not only kill cancer cells but also stimulate the immune system, among them, necroptosis is a classical immunogenic form of cell death. In our study, we discovered that by targeting RIP3, Jaspine B derivative C8 induces necroptosis and initiates cell death, and this effect can be reversed by knockout of RIP3. Furthermore, RIP3 initiates autophagy and binds to p62 to inhibit autophagic flux. Additionally, the autophagy process mediated by RIP3 activates the Nrf2 signaling pathway via the formation of the p62/Keap1 complex. Early autophagy inhibitors enhance necroptosis by impending the accumulation of p62 and restraining the activation of Nrf2, whereas late autophagy inhibitors partially prevent C8-induced necroptosis. Notably, the immunogenic form of cell death induced by C8 did not affect tumor immunity. Overall, C8 functions as a RIP3 activator to suppress the development of gastric cancer. Upon activation, RIP3 regulates p62-mediated autophagic flux and the Nrf2 signaling pathway through the RIP3/p62/Keap1 axis.
    Keywords:  Autophagy; Immune system; Jaspine B derivative; Nrf2; RIP3/p62/Keap1 axis
    DOI:  https://doi.org/10.1016/j.bioorg.2024.107937
  19. Front Immunol. 2024 ;15 1488020
    Autophagy and proteasomes in thymic epithelial cells: essential bulk protein degradation systems for immune homeostasis maintenance.
    Noritaka Yamaguchi, Yuki Takakura, Taishin Akiyama.
      The thymus is a central organ that controls T cell development. Thymic epithelial cells (TECs) create a unique microenvironment essential for the differentiation of major histocompatibility complex (MHC)-restricted and self-tolerant T cells. TECs present a complex of self-peptides and MHC molecules (self-pMHCs) to immature T cells and regulate their survival and differentiation based on their affinity for self-pMHCs. The processing of self-peptides in TECs depends on bulk protein degradation systems, specifically autophagy and proteasomes. Studies using autophagy- and proteasome-deficient mouse models have demonstrated that these degradation systems in TECs are indispensable for maintaining immune homeostasis. Although autophagy and proteasomes are ubiquitous in nearly all eukaryotic cells, TECs exhibit unique characteristics in their autophagy and proteasome functions. Autophagy in TECs is constitutively active and independent of stress responses, while TEC proteasomes contain specialized catalytic subunits. This review summarizes the distinctive characteristics of autophagy and proteasomes in TECs and their roles in immune system regulation.
    Keywords:  T cells; autophagy; proteasomes; thymic epithelial cells; thymus
    DOI:  https://doi.org/10.3389/fimmu.2024.1488020
  20. Aging Cell. 2024 Nov 07. e14404
    Overexpression of TECPR1 improved cognitive function of P301S-tau mice via activation of autophagy in the early and late process.
    Ting Li, Ruijuan Liu, Ye He, Bingge Zhang, Xuexiang Rui, Xifei Yang, Jian-Zhi Wang, Juan Zeng, Gang Li, Xiao Li, Gong-Ping Liu.
      Autophagy disorders in AD patients and animal models were well known, however, the effect of P301S-tau on autophagy is not clear. Here, we found that autophagy related protein Tectonin Beta-Propeller Repeat-Containing Protein 1 (TECPR1) decreased in the hippocampus of P301S-tau transgenic mice by proteomics, which was proved in vivo and in vitro, and P301S-tau induced autophagic deficits in early and late process. TECPR1 overexpression attenuated P301S-tau induced autophagy defects via promoting autophagosome generation and autophagosome and lysosomes fusion. We also found that TECPR1 overexpression ameliorated the behavior disorders of P301S-tau mice with promoting tau degradation, improving synaptic plasticity and neuron loss. Lastly, CQ or 3-MA treatment reversed TECPR1 induced improvement effects on autophagic and cognitive disorders, further proved that, TECPR1 activated the early and late process of autophagy to ameliorate the cognition of P301S-tau mice. Our data suggest that TECPR1 is a potential therapy target for AD.
    Keywords:  TECPR1; autophagy; cognitive function; synapse; tau
    DOI:  https://doi.org/10.1111/acel.14404
  21. Front Immunol. 2024 ;15 1460023
    Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis.
    Lin Lin, Yumeng Lin, Zhongyu Han, Ke Wang, Shuwei Zhou, Zhanzhan Wang, Siyu Wang, Haoran Chen.
      Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy.
    Keywords:  COPD; apoptosis; autophagosome; autophagy; pulmonary diseases
    DOI:  https://doi.org/10.3389/fimmu.2024.1460023
  22. Heliyon. 2024 Nov 15. 10(21): e38959
    The role of autophagy in brain health and disease: Insights into exosome and autophagy interactions.
    Hai-Dong Wang, Chao-Liang Lv, Lei Feng, Jin-Xiu Guo, Shi-Yuan Zhao, Pei Jiang.
      Effective management of cellular components is essential for maintaining brain health, and studies have identified several crucial biological processes in the brain. Among these, autophagy and the role of exosomes in cellular communication are critical for brain health and disease. The interaction between autophagy and exosomes in the nervous system, as well as their contributions to brain damage, have garnered significant attention. This review summarizes that exosomes and their cargoes have been implicated in the autophagy process in the pathophysiology of nervous system diseases. Furthermore, the onset and progression of neurological disorders may be affected by autophagy regulation of the secretion and release of exosomes. These findings may provide new insights into the potential mechanism by which autophagy mediates different exosome secretion and release, as well as the valuable biomedical applications of exosomes in the prevention and treatment of various brain diseases by targeting autophagy.
    Keywords:  Autophagy; Brain; Brain disease; Exosomes; Nervous system
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e38959
  23. Autophagy. 2024 Nov 08.
    Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
    Moumita Roy, Sumangal Nandy, Elena Marchesan, Chayan Banerjee, Rupsha Mondal, Federico Caicci, Elena Ziviani, Joy Chakraborty.
      Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this phenomenon. Through in vitro biochemical assays and imaging, we have found that VDAC1-PHB2 interaction increases during mitochondrial depolarization. Subsequently, this interaction enhances the efficiency of PHB2 exposure and mitophagy. To investigate the relevance in vivo, we utilized porin (equivalent to VDAC1) knockout Drosophila line. Our findings demonstrate that during mitochondrial stress, porin is essential for Phb2 exposure, Phb2-Atg8 interaction and mitophagy. This study highlights that VDAC1 predominantly synchronizes efficient PHB2 exposure through mitochondrial rupture sites during mitophagy. These findings may provide insights to understand progressive neurodegeneration.
    Keywords:  Neurodegeneration; PHB2-LC3 interaction; PINK1-PRKN; parkinson disease; porin; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2024.2426116
  24. Exp Anim. 2024 Nov 13.
    Morphological analysis of autophagy in axonal degeneration in gracile axonal dystrophy mice.
    Yusuke Tokuhara, Shinichiro Ukon, Shohei Watanabe, Yoshiki Tatsumi, Hiroo Yoshikawa, Masaki Ohmuraya, Takashi Kimura.
      Gracile axonal dystrophy (gad) mutant mice present with autosomal recessive inherited sensory ataxia in the early stages, followed by age-dependent motor ataxia. This phenotype is caused by a mutation in the ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) gene and leads to a lack of expression of UCH-L1 protein, which is related with the autophagy pathway and the ubiquitin-proteasome system (UPS). To elucidate the pathophysiology of abnormal protein accumulation in gad mice, we focused on macroautophagy. Using electron microscopy, we detected a double-membrane structure, which was characteristic of autophagosomes, in gad mice. In addition, on immunohistochemistry to investigate the expression levels of autophagy-related proteins in the gracile nuclei of the gad mouse, we found upregulation of LC3 and p62 but not LAMP-2A. These results suggested that a lack of UCH-L1 expression might induce the formation of autophagosomes, but the resulting autophagy flux might be disturbed.
    Keywords:  autophagy; gracile axonal dystrophy mouse; ubiquitin carboxyl-terminal hydrolase isozyme L1; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1538/expanim.24-0041
  25. Am J Respir Cell Mol Biol. 2024 Nov 08.
    Enhanced Gαq Signaling in TSC2-deficient Cells Is Required for Their Neoplastic Behavior.
    Aurelie Trefier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof.
      Inherited or sporadic loss of the TSC2 gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage ('LAM cells'). Their aberrant growth is attributed to increased activity of 'mechanistic target of rapamycin complex 1' (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM, but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G-protein coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in TSC2-deficient cells remained unknown. Using a human pluripotent stem cell-derived in vitro model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and pro-neoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking TSC2 demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared to wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in TSC2-deleted cells was independent of mTOR activity, and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent pro-neoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.
    Keywords:  Gαq; Lymphangioleiomyomatosis; Mechanistic target of rapamycin; Tuberous sclerosis complex; Urotensin-II receptor
    DOI:  https://doi.org/10.1165/rcmb.2024-0111OC
  26. EMBO J. 2024 Nov 12.
    Calcium signaling from damaged lysosomes induces cytoprotective stress granules.
    Jacob Duran, Jay E Salinas, Rui Ping Wheaton, Suttinee Poolsup, Lee Allers, Monica Rosas-Lemus, Li Chen, Qiuying Cheng, Jing Pu, Michelle Salemi, Brett Phinney, Pavel Ivanov, Alf Håkon Lystad, Kiran Bhaskar, Jaya Rajaiya, Douglas J Perkins, Jingyue Jia.
      Lysosomal damage induces stress granule (SG) formation. However, the importance of SGs in determining cell fate and the precise mechanisms that mediate SG formation in response to lysosomal damage remain unclear. Here, we describe a novel calcium-dependent pathway controlling SG formation, which promotes cell survival during lysosomal damage. Mechanistically, the calcium-activated protein ALIX transduces lysosomal damage signals to SG formation by controlling eIF2α phosphorylation after sensing calcium leakage. ALIX enhances eIF2α phosphorylation by promoting the association between PKR and its activator PACT, with galectin-3 inhibiting this interaction; these regulatory events occur on damaged lysosomes. We further find that SG formation plays a crucial role in promoting cell survival upon lysosomal damage caused by factors such as SARS-CoV-2ORF3a, adenovirus, malarial pigment, proteopathic tau, or environmental hazards. Collectively, these data provide insights into the mechanism of SG formation upon lysosomal damage and implicate it in diseases associated with damaged lysosomes and SGs.
    Keywords:  ALG2-ALIX; Calcium-dependent Pathway; Lysosomal Damage; PACT-PKR-eIF2α; Stress Granules
    DOI:  https://doi.org/10.1038/s44318-024-00292-1
  27. Int J Mol Sci. 2024 Oct 27. pii: 11527. [Epub ahead of print]25(21):
    High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias.
    Amreen Salwa, Alessandra Ferraresi, Letizia Vallino, Chinmay Maheshwari, Riccardo Moia, Gianluca Gaidano, Ciro Isidoro.
      Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient's prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of MAP1LC3B (along with that of BECN1 and with low expression of p62/SQSTM1) and the high expression of BNIP3 (along with that of PRKN and of MAP1LC3B), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers HK2, PFKM, and PKM correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy-mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management.
    Keywords:  TCGA; Warburg effect; autophagy; bioinformatics; leukemia; mitochondria; overall survival; personalized medicine
    DOI:  https://doi.org/10.3390/ijms252111527
  28. Int J Mol Sci. 2024 Oct 30. pii: 11678. [Epub ahead of print]25(21):
    IL-32γ Induced Autophagy Through Suppression of MET and mTOR Pathways in Liver Tumor Growth Inhibition.
    Ji-Won Seo, Yong-Sun Lee, In-Sook Jeon, Ji-Eun Yu, Jun-Sang Yoo, Ja-Keun Koo, Dong-Ju Son, Jae-Suk Yoon, Sang-Bae Han, Do-Young Yoon, Yoon-Seok Roh, Jin-Tae Hong, Jung-Hyun Shim.
      Interleukin-32γ (IL-32γ) has diverse functions in various malignancies. In this study, we investigated the role of IL-32γ in autophagy induction in liver cancer cells and delineated the underlying mechanisms. We found that the increased IL-32γ expression inhibited the growth, cell cycle progression, and migration of HepG2 and Hep3B cell lines; it also decreased the expression of related proteins. Furthermore, the IL-32γ overexpression induced autophagy, as indicated by the number of puncta, the expression of LC3, and the expression of autophagy-related markers. The expression levels of LAMP1, a protein essential for autophagosome formation, and colocalization with LC3 also increased. Big data analysis revealed that the expression of MET, a well-known target of autophagy, and the expression of mTOR and mTOR-related proteins were decreased by the IL-32γ overexpression. The combination treatment of MET inhibitor, cabozantinib (2 µM), and IL-32γ overexpression further increased the number of puncta, the colocalization of LC3 and LAMP1, and the expression of autophagy-related proteins. In vivo, liver tumor growth was suppressed in the IL-32γ-overexpressing mouse model, and autophagy induction was confirmed by the increased expression of LC3 and LAMP1 and the decreased expression of autophagy pathway markers (MET and mTOR). Autophagy was also decreased in the liver tumor sample of human patients. ROC curve and spearman analysis revealed that the expression levels of LC3 and IL-32γ were significantly correlated in human tumor serum and tissues. Therefore, IL-32γ overexpression induced autophagy in liver tumors through the suppression of MET and mTOR pathways critical for tumor growth inhibition.
    Keywords:  IL-32γ; MET; autophagy; liver cancer; mTOR
    DOI:  https://doi.org/10.3390/ijms252111678
  29. Heliyon. 2024 Nov 15. 10(21): e39752
    TPC1 regulates melanoma tumourigenesis via mTORC1 and TFEB.
    Xuhui Jin, Ali A Hanbashi, Faroq Kamli, Xiaoqi Pan, Colin R Goding, John Parrington.
      The major cause of death in cancer patients is a combination of metastatic dissemination combined with therapy resistance. Over recent years, intratumour phenotypic heterogeneity arising from the bi-directional interplay between plastic cancer cells and the microenvironment has been identified as key to disease progression. Most notably metastatic outgrowth and resistance to targeted therapies are frequently associated with activity of mTORC1, a key metabolic hub that promotes protein synthesis and proliferation in the presence of nutrients. Yet while the regulation of mTORC1 by amino acids and glucose availability is well characterized, whether other mechanisms are important in controlling mTORC1 and its downstream signalling is less well understood. Here we show, using the murine B16-F0 melanoma cell line as a model, that mTORC1 activity is decreased following the knockout (KO) of TPC1, a cation channel localised to early and recycling endosomes. Consequently, TPC1 KO melanoma cells exhibit reduced proliferation and invasiveness, as well as increased pigmentation associated with nuclear localisation of the MITF-related transcription factor TFEB. Our results demonstrate that the knockout of TPC1 has induced significant tumour-suppressive effects in melanoma, during which the altered activity of mTORC1 and TFEB play the key roles. The results help us further understand the link between mTORC1 and endolysosomal ion channels, and reveal that TPC1 controls melanoma progression and represents a potential therapeutic target.
    Keywords:  MITF; Melanoma; TFEB; TPC1; mTORC1
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e39752
  30. Cells. 2024 Nov 04. pii: 1816. [Epub ahead of print]13(21):
    NKX3-2 Induces Ovarian Cancer Cell Migration by HDAC6-Mediated Repositioning of Lysosomes and Inhibition of Autophagy.
    Alessandra Ferraresi, Ian Ghezzi, Amreen Salwa, Andrea Esposito, Danny N Dhanasekaran, Ciro Isidoro.
      Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of NKX3-2 positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of ATG7 or BECN1, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment.
    Keywords:  BAPX1; HDAC6; autophagy; epithelial to mesenchymal transition; lysophosphatidic acid; lysosome; ovarian cancer
    DOI:  https://doi.org/10.3390/cells13211816
  31. J Adv Res. 2024 Nov 07. pii: S2090-1232(24)00501-0. [Epub ahead of print]
    Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway.
    Ze Chen, Mingze Tang, Zewei Wu, Yongcong Lin, Cuixi Wu, Hong Huang, Jianmao Chen, Zhaohua Zhu, Yongming Liu, Súan Tang, Changhai Ding, Weiyu Han.
      INTRODUCTION: Cartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA.OBJECTIVES: This study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis.
    METHODS: Proteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a in vitro and in vivo. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis in vivo. Histological analysis was employed to demonstrate cartilage damage.
    RESULTS: Rab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both in vitro and in vivo, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis.
    CONCLUSION: The augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.
    Keywords:  Apoptosis; Autophagy; Osteoarthritis; Rab1a; mTORC1
    DOI:  https://doi.org/10.1016/j.jare.2024.11.009
  32. Sci Immunol. 2024 Nov 08. 9(101): eadi7907
    Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.
    Shengxiang Sun, Miki Hodel, Xiang Wang, Javier De Vicente, Talin Haritunians, Anketse Debebe, Chen-Ting Hung, Changqing Ma, Atika Malique, Hoang N Nguyen, Maayan Agam, Michael T Maloney, Marisa S Goo, Jillian H Kluss, Richa Mishra, Jennifer Frein, Amanda Foster, Samuel Ballentine, Uday Pandey, Justin Kern, Shaohong Yang, Emebet Mengesha, Iyshwarya Balasubramanian, Annie Arguello, Anthony A Estrada, Nan Gao, Inga Peter, Dermot P B McGovern, Anastasia G Henry, Thaddeus S Stappenbeck, Ta-Chiang Liu.
      LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.
    DOI:  https://doi.org/10.1126/sciimmunol.adi7907
  33. Sci Rep. 2024 Nov 15. 14(1): 28118
    Activation of the mTOR pathway enhances PPARγ/SREBP-mediated lipid synthesis in human meibomian gland epithelial cells.
    Ikhyun Jun, Young Joon Choi, Bo-Rahm Kim, Hyung Keun Lee, Kyoung Yul Seo, Tae-Im Kim.
      The involvement of the mechanistic targets of rapamycin (mTOR) pathway in lipid metabolism has been recently elucidated. However, its specific role in the Meibomian gland, where lipid metabolism is significant, remains not fully understood. We investigated the role of mTOR signaling system in the lipogenesis and differentiation of human meibomian gland epithelial cells (HMGECs). Treatment of HMGECs with rapamycin resulted in a reduction in lipid synthesis and the expression of PPARγ and SREBP-1, the major regulators of lipid synthesis. The phosphorylation of p70S6kinase and AKT, which are downstream signals of mTOR complexes 1 and 2, respectively, decreased following rapamycin treatment. In addition, when both mTOR complex 1 and 2 were suppressed using siRNA, there was a significant reduction in the expression of PPARγ and SREBP-1, along with a decrease in lipid synthesis in HMGECs. Our findings suggest that inhibiting the mTOR pathway diminishes the differentiation and adipogenesis of meibomian gland epithelial cells, and both mTOR complexes 1 and 2 appear to play a role in this activity.
    DOI:  https://doi.org/10.1038/s41598-024-73969-6
  34. Trends Cell Biol. 2024 Nov 14. pii: S0962-8924(24)00227-7. [Epub ahead of print]
    TFEB links the cGAS-STING pathway to lysosome biogenesis.
    Yaping Meng, Xinran Li, Haoxing Xu.
      The cGAS-STING pathway senses the level of double-stranded (ds)DNA in the cytosol, and is required for innate immunity through its effector, TBK1. A recent study by Lv et al. reports that STING activation also simultaneously promotes lysosomal biogenesis by inducing nuclear translocation of the transcription factors TFEB/TFE3 independent of TBK1.
    Keywords:  STING; TFEB; cGAS; lysosome
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.011
  35. Sci Rep. 2024 11 09. 14(1): 27312
    Stenosing Crohn's disease patients display gut autophagy/oxidative stress imbalance.
    Leonardo Schirone, Maria Carla Di Paolo, Daniele Vecchio, Cristina Nocella, Alessandra D'Amico, Riccardo Urgesi, Lorella Pallotta, Gianfranco Fanello, Giuseppe Villotti, Maria Giovanna Graziani, Mariangela Peruzzi, Elena De Falco, Roberto Carnevale, Sebastiano Sciarretta, Giacomo Frati, Cristiano Pagnini.
      In this pilot study, we assessed the role of autophagy in Crohn's Disease (CD), particularly in patients with a stenosing phenotype. Through the analysis of biopsied specimens from 36 patients, including 11 controls and 25 CD patients, categorized into inflammatory and stenosing groups, we identified a significant reduction in the autophagosomal marker Lc3b-II in patients with active inflammation and stenosis. This was paralleled by an increase in oxidative stress markers, including sNOX2-dp and H2O2, and a decrease in the antioxidant capacity measured by HBA, suggesting an imbalance in autophagy and oxidative stress mechanisms. Additionally, our findings show a correlation between autophagy markers and oxidative stress levels, indicating that autophagy dysfunction may play a pivotal role in CD and in the progression of a stenosing disease phenotype, by failing to eliminate detrimental molecules and pathogenic bacteria, thereby promoting fibrosis. This study is the first to demonstrate in vivo autophagy inhibition in stenosing CD patients and suggests that stimulating autophagic processes could offer a new avenue for the prevention and treatment of intestinal fibrosis in CD. Our results highlight the importance of exploring the interactions between autophagy, the fibrotic process, and the inflammatory cascade, opening avenues for potential therapeutic interventions in CD management.
    Keywords:  Autophagic Dysregulation; Fibrostenotic Complications; Inflammatory Bowel Disease (IBD); Reactive Oxygen Species (ROS); Redox Homeostasis
    DOI:  https://doi.org/10.1038/s41598-024-79308-z
  36. Cell Death Dis. 2024 Nov 13. 15(11): 824
    STING orchestrates microglia polarization via interaction with LC3 in autophagy after ischemia.
    Lingqi Kong, Pengfei Xu, Nan Shen, Wenyu Li, Rui Li, Chunrong Tao, Guoping Wang, Yan Zhang, Wen Sun, Wei Hu, Xinfeng Liu.
      Autophagy has both protective and pathogenetic effects on injury caused by cerebral ischemia/reperfusion (I/R). Our previous research has indicated that stimulator of interferon genes (STING) could orchestrate microglia polarization following middle cerebral artery occlusion. However, it remains largely unexplored whether STING balances microglial polarization by regulating autophagy in brain I/R injury. Here, STING was observed to show an up-regulation in the microglia from mice subjected to experimental ischemic stroke. Strikingly, the deletion of STING led to the significant skewness of microglia activated by ischemia from a pro- to anti-inflammatory state and substantially alleviated ischemia-induced infarction and neuronal injury. In addition, STING-null mice can restore long-term neurobehavioral function. Then, the crosstalk between neuroinflammation and microglia autophagy was analyzed. The differential activity of autophagy in wild-type and STING-knockout (KO) mice or primary microglia was largely reversed when STING was restored in microglia. Irritating autophagy by rapamycin skewed the anti‑inflammatory state induced by STING-KO to a pro‑inflammatory state in microglia. Furthermore, microtubule-associated protein light-chain-3 (LC3) was identified as the key factor in the STING regulation of autophagy by glutathione-S-transferase (GST) pull-down analysis. Mechanically, STING can directly interact with LC3 through the STING transmembrane domain (1-139aa). Herein, current data determine the pivotal role of autophagy, specifically via LC3 protein, in the regulation of microglial phenotypic transformation by STING. These findings may provide a possible treatment target for delaying the progression of ischemic stroke.
    DOI:  https://doi.org/10.1038/s41419-024-07208-1
  37. J Cell Biol. 2025 Feb 03. pii: e202403178. [Epub ahead of print]224(2):
    Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.
    Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E Clausen, Benjamin Voisin, Christopher G Mueller, Frédéric Gros, Vincent Flacher.
      Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.
    DOI:  https://doi.org/10.1083/jcb.202403178
  38. J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02454-2. [Epub ahead of print] 107952
    MTOR maintains endothelial cell integrity to limit lung vascular injury.
    Michelle Warren Millar, Rauf A Najar, Spencer A Slavin, Mohammad Shadab, Imran Tahir, Zahra Mahamed, Xin Lin, Jun-Ichi Abe, Terry W Wright, David A Dean, Fabeha Fazal, Arshad Rahman.
      The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify Mechanistic Target of Rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface VE-Cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-Cadherin and VEGFR2 levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-Cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-Cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR cDNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.
    Keywords:  Endothelial cells; MTOR; VE-Cadherin; and VEGFR2; gene therapy; lung vascular injury
    DOI:  https://doi.org/10.1016/j.jbc.2024.107952
  39. Eur J Pharmacol. 2024 Nov 12. pii: S0014-2999(24)00790-8. [Epub ahead of print] 177100
    Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy.
    Ruixin Zhang, Qi Fang, Lei Yao, Xiaolan Yu, Xingyun Liu, Mengting Zhan, Deng Liu, Qi Yan, Jian Du, Lijian Chen.
      BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms.METHODS: C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 minutes of 70% hepatic ischemia. After 6 hours of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R).
    RESULTS: Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX.
    CONCLUSION: The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R.
    Keywords:  Apoptosis; Hepatic ischemia-reperfusion injury; Mitochondria; PINK1/Parkin; Taxifolin
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177100
  40. FEBS J. 2024 Nov 08.
    Atg2 controls Drosophila hematopoiesis through the PVR/TOR signaling pathways.
    Bo Qin, Hongmei Xue, Xiaoran Wang, Hyonil Kim, Li Hua Jin.
      The hematopoietic system of Drosophila is a well-established genetic model for studying hematopoiesis mechanisms, which are strictly regulated by multiple signaling pathways. Autophagy-related 2 (Atg2) protein is involved in autophagosome formation through its lipid transfer function; however, other functions in animal development, especially the role of Atg2 in maintaining hematopoietic homeostasis, are unclear. Here, we show that Atg2 knockdown in the cortical zone (CZ) induced the proliferation and differentiation of mature plasmatocytes and disrupted progenitor maintenance in the medullary zone (MZ). We also observed the differentiation of lamellocytes among circulating hemocytes and in the lymph gland, which is rarely observed in healthy larvae. The above results on hematopoiesis disorders are due to Atg2 regulating the Drosophila PDGF/VEGF receptor (PVR) and target of rapamycin (TOR) in the CZ of lymph gland. In conclusion, we identified Atg2 as a previously undescribed regulator of hematopoiesis. Understanding the mechanism of maintenance of hematopoietic homeostasis in Drosophila will help us better evaluate human blood disorder-related diseases.
    Keywords:  Atg2; Drosophila hematopoiesis; lamellocyte; lymph gland
    DOI:  https://doi.org/10.1111/febs.17288
  41. Autophagy. 2024 Nov 07.
    Avian TRIM13 attenuates antiviral innate immunity by targeting MAVS for autophagic degradation.
    Peng Zhou, Qingxiang Zhang, Yueshan Yang, Dong Chen, Anan Jongkaewwattana, Hui Jin, Hongbo Zhou, Rui Luo.
      MAVS (mitochondrial antiviral signaling protein) is a crucial adaptor in antiviral innate immunity that must be tightly regulated to maintain immune homeostasis. In this study, we identified the duck Anas platyrhynchos domesticus TRIM13 (ApdTRIM13) as a novel negative regulator of duck MAVS (ApdMAVS) that mediates the antiviral innate immune response. Upon infection with RNA viruses, ApdTRIM13 expression increased, and it specifically binds to ApdMAVS through its TM domain, facilitating the degradation of ApdMAVS in a manner independent of E3 ligase activity. Furthermore, ApdTRIM13 recruits the autophagic cargo receptor duck SQSTM1 (ApdSQSTM1), which facilitates its interaction with ApdMAVS independent of ubiquitin signaling, and subsequently delivers ApdMAVS to phagophores for degradation. Depletion of ApdSQSTM1 reduces ApdTRIM13-mediated autophagic degradation of ApdMAVS, thereby enhancing the antiviral immune response. Collectively, our findings reveal a novel mechanism by which ApdTRIM13 regulates type I interferon production by targeting ApdMAVS for selective autophagic degradation mediated by ApdSQSTM1, providing insights into the crosstalk between selective autophagy and innate immune responses in avian species.
    Keywords:  Antiviral immunity; ApdMAVS; ApdTRIM13; SQSTM1; autophagic degradation
    DOI:  https://doi.org/10.1080/15548627.2024.2426114
  42. Autophagy. 2024 Nov 08.
    PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
    Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue.
      Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.
    Keywords:  Colorectal cancer; deferiprone; iron chelation; minocycline; mitochondrial iron; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2425594
  43. Cell Death Differ. 2024 Nov 12.
    Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance.
    Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu.
      Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.
    DOI:  https://doi.org/10.1038/s41418-024-01411-5
  44. Science. 2024 Nov 15. 386(6723): 768-776
    Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy.
    Cristian Prieto-Garcia, Vigor Matkovic, Thorsten Mosler, Congxin Li, Jie Liang, James A Oo, Felix Haidle, Igor Mačinković, Alfredo Cabrera-Orefice, Rayene Berkane, Giulio Giuliani, Fenfen Xu, Anne-Claire Jacomin, Ines Tomaskovic, Marion Basoglu, Marina E Hoffmann, Rajeshwari Rathore, Ronay Cetin, Doha Boutguetait, Süleyman Bozkurt, María Clara Hernández Cañás, Mario Keller, Jonas Busam, Varun Jayeshkumar Shah, Ilka Wittig, Manuel Kaulich, Petra Beli, Wojciech P Galej, Ingo Ebersberger, Likun Wang, Christian Münch, Alexandra Stolz, Ralf P Brandes, William Ka Fai Tse, Stefan Eimer, Didier Y R Stainier, Stefan Legewie, Kathi Zarnack, Michaela Müller-McNicoll, Ivan Dikic.
      RNA splicing enables the functional adaptation of cells to changing contexts. Impaired splicing has been associated with diseases, including retinitis pigmentosa, but the underlying molecular mechanisms and cellular responses remain poorly understood. In this work, we report that deficiency of ubiquitin-specific protease 39 (USP39) in human cell lines, zebrafish larvae, and mice led to impaired spliceosome assembly and a cytotoxic splicing profile characterized by the use of cryptic 5' splice sites. Disruptive cryptic variants evaded messenger RNA (mRNA) surveillance pathways and were translated into misfolded proteins, which caused proteotoxic aggregates, endoplasmic reticulum (ER) stress, and, ultimately, cell death. The detrimental consequence of splicing-induced proteotoxicity could be mitigated by up-regulating the ubiquitin-proteasome system and selective autophagy. Our findings provide insight into the molecular pathogenesis of spliceosome-associated diseases.
    DOI:  https://doi.org/10.1126/science.adi5295
  45. J Biomol Struct Dyn. 2024 Nov 13. 1-8
    Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.
    Robert M Vaughan, Bradley M Dickson, Katie R Martin, Jeffrey P MacKeigan.
      Kinase domains are highly conserved within proteins in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. ULK1 and ULK2 are serine/threonine kinases that serve important roles in autophagy, an intracellular recycling process capable of degrading proteins and organelles via fusion with lysosomes. ULK1/2 are emerging as therapeutic targets in human cancer, particularly KRAS-driven malignancies. Here, we performed molecular dynamics (MD) simulations to hypothesize bound poses for the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the phosphate-binding loop (P-loop) are also associated with ULK-101 inhibitor binding and exit from ULK2. Together, our data support a model to explain ULK-101 potency toward ULK1/2.
    Keywords:  ULK-101; ULK1; ULK2; adaptive biasing; autophagy; kinase; molecular dynamics simulations; small molecule inhibitor
    DOI:  https://doi.org/10.1080/07391102.2024.2425833
  46. Nat Commun. 2024 Nov 12. 15(1): 9797
    HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
    Annmary Paul Erinjeri, Xunyan Wang, Rhianna Williams, Riccardo Zenezini Chiozzi, Konstantinos Thalassinos, Johnathan Labbadia.
      Increased activity of the heat shock factor, HSF-1, suppresses proteotoxicity and enhances longevity. However, the precise mechanisms by which HSF-1 promotes lifespan are unclear. Using an RNAi screen, we identify ubiquilin-1 (ubql-1) as an essential mediator of lifespan extension in worms overexpressing hsf-1. We find that hsf-1 overexpression leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan. Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.
    DOI:  https://doi.org/10.1038/s41467-024-54136-x
  47. Cell Mol Life Sci. 2024 Nov 15. 81(1): 454
    αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury.
    Xuying Zhu, Qisheng Lin, Yuanting Yang, Shu Li, Xinghua Shao, Weiming Zhang, Hong Cai, Jialin Li, Jingkui Wu, Kaiqi Zhang, Chaojun Qi, Minfang Zhang, Xiajing Che, Leyi Gu, Zhaohui Ni.
      Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway.
    Keywords:  Acute kidney injury; Contrast media; FoxO3; Klotho; Mitophagy
    DOI:  https://doi.org/10.1007/s00018-024-05473-z
  48. Int J Mol Sci. 2024 Oct 26. pii: 11504. [Epub ahead of print]25(21):
    Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster.
    Aaron A Bearden, Emily M Stewart, Candace C Casher, Meredith A Shaddix, Amber C Nobles, Robin J Mockett.
      Various dietary supplements have been shown to extend the life span of Drosophila melanogaster, including several that promote autophagy, such as rapamycin and spermidine. The goal of the study presented here was to test numerous additional potential anti-aging supplements, primarily inhibitors of the target of rapamycin (TOR) and/or phosphatidylinositol 3-kinase (PI3K). Using a single, comparatively long-lived y w test strain, screening was performed in male flies supplemented either throughout adulthood or, in a few cases, beginning in middle or late adult life, with concentrations spanning 4-6 orders of magnitude in most cases. Supplementation with PP242 and deferiprone, an iron chelator, beginning in late adult life had no positive effect on life span. Lifelong supplementation with Ku-0063794, LY294002, PX-866-17OH, Torin2 and WYE-28 had no effect at any dose. Rapamycin, spermidine and wortmannin all had significant life-shortening effects at the highest doses tested. AZD8055, PI-103 hydrochloride and WYE-132 yielded slight beneficial effects at 1-2 doses, but only 100 nM AZD8055 was confirmed to have a minor (1.3%) effect in a replicate experiment, which was encompassed by other control groups within the same study. These compounds had no effect on fly fecundity (egg laying) or fertility (development of progeny to adulthood), but equivalent high doses of rapamycin abolished fertility. The solvent DMSO had no significant effect on life span at the concentrations used to solubilize most compounds in the fly medium, but it drastically curtailed both survival and fertility at higher concentrations. 2-Hydroxypropyl-β-cyclodextrin also failed to extend the life span when provided throughout adulthood or beginning in mid-adult life. Collectively, the results suggest that inhibition of the TOR/PI3K pathway and autophagy through dietary intervention is not a straightforward anti-aging strategy in Drosophila and that further extension of life is difficult in comparatively long-lived flies.
    Keywords:  Drosophila; TOR inhibition; aging; life span; rapamycin
    DOI:  https://doi.org/10.3390/ijms252111504
  49. Adv Sci (Weinh). 2024 Nov 08. e2409498
    The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce RNH1/miR-99a/mTOR-Mediated Autophagy and Apoptosis.
    Hui-Fang Hu, Jia-Ying Fu, Lei Han, Gui-Bin Gao, Wei-Xia Zhang, Si-Ming Yu, Nan Li, Yang-Jia Li, Yi-Fan Lu, Xiao-Feng Ding, Yun-Long Pan, Yang Wang, Qing-Yu He.
      The mammalian target of rapamycin (mTOR) is a critical signaling hub for sustaining cancer survival. Targeting mTOR and inducing autophagic cell death downstream of it represent promising therapeutic strategies for cancer prevention. A US Food and Drug Administration-approved drug library containing 616 small molecules is used to screen anticancer drugs against colorectal cancer (CRC) cells that rely on mTOR. This led to the identification of an antipsychotic drug aripiprazole, which significantly induced mTOR inhibition and autophagic apoptosis in CRC, in vitro and in vivo. The use of drug affinity response target stability identified lysosome-associated membrane protein 2A (LAMP2a) as a direct target of aripiprazole. LAMP2a-deficient CRC cells are refractory to aripiprazole. High LAMP2a expression is associated with poor survival of patients with CRC and negatively correlated with expression of ribonuclease inhibitor 1 (RNH1), which is later confirmed as a novel substrate of LAMP2a. Mechanistically, aripiprazole bound to the Lys401-His404 of LAMP2a and repressed its activity, subsequently inactivating RNH1/miR-99a/mTOR signaling and inducing autophagy-mediated apoptosis, thereby suppressing tumorigenesis. Liposome-mediated delivery of aripiprazole in combination with fluorouracil elicited superior therapeutic benefits in CRC, as compared to single treatments, thereby highlighting that aripiprazole may be repurposed as a novel therapeutic agent for CRC treatment.
    Keywords:  5‐FU; LAMP2a; aripiprazole; autophagy; mTOR
    DOI:  https://doi.org/10.1002/advs.202409498
  50. Methods Mol Biol. 2025 ;2878 211-221
    Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
    Pedro A Dionísio, Vilma A Sardão, Nuno Raimundo.
      Live cell imaging is a robust method to visualize dynamic cellular structures, especially organelles with network-like structures such as mitochondria. In this regard, mitochondrial dynamics, namely mitochondrial fission and fusion, are highly dynamic processes that regulate mitochondrial size and morphology depending on a plethora of cellular cues. Likewise, lysosome size and distribution may hint at their function and state.Here, we describe how to perform live cell confocal imaging using commercially available organelle dyes (MitoTracker, LysoTracker), followed by either 2D or 3D analyses of mitochondrial morphology/network connectivity and lysosomal morphology using the freely available Mitochondria Analyzer plugin for ImageJ/Fiji.
    Keywords:  Cell imaging; Fluorescent probes; LysoTracker; Lysosomes; Microscopy; MitoTracker; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/978-1-0716-4264-1_11
  51. Cell Commun Signal. 2024 Nov 07. 22(1): 535
    RNF13 protects neurons against ischemia-reperfusion injury via stabilizing p62-mediated Nrf2/HO-1 signaling pathway.
    Qiangping Wang, Shuang Li, Wenjie Wu, Wenke Zhou, Kaixuan Yan, Zhen Liu, Lanlan Yan, Baoping Zheng, Fangcheng Zhang, Xiaobing Jiang, Youfan Ye, Haijun Wang.
      BACKGROUND: Cerebral ischemia/reperfusion injury (CIRI), a common, universal clinical problem that costs a large proportion of the economic and disease burden. Identifying the key regulators of cerebral I/R injury could provide potential strategies for clinically improving the prognosis of stroke. Ring finger protein 13 (RNF13) has been proven to be involved in the inflammatory response. Here, we aimed to identify the role of RNF13 in cerebral I/R injury and further reveal its immanent mechanisms.METHODS: The CRISPR/Cas9 based knockout mice, RNA sequencing, mass spectrometry, co-immunoprecipitation, GST-pull down, immunofluorescent staining, western blot, RT-PCR were used to investigate biodistribution, function and mechanism of RNF13 during cerebral I/R injury.
    RESULTS: In the present study, we found that RNF13 was significantly up-regulated in patients, mice and primary neurons after I/R injury. Deficiency of RNF13 aggravated I/R-induced neurological impairment, inflammatory response and apoptosis while overexpression of RNF13 inhibited I/R injury. Mechanistically, this inhibitory effect of RNF13 during I/R injury was confirmed to be dependent on the blocking of TRIM21-mediated autophagy-dependent degradation of p62 and the stabilization of the p62-mediated Nrf2/HO-1 signaling pathway.
    CONCLUSION: RNF13 is a crucial regulator of cerebral I/R injury that plays its role in inhibiting cell apoptosis and inflammatory response by preventing the autophagy-medicated degradation of the p62/Nrf2/HO-1 signaling pathway via blocking the interaction of TRIM21-p62 complex. Therefore, RNF13 represents a potential pharmacological target in acute ischemia stroke therapy.
    Keywords:  Ischemia reperfusion (I/R) injury; Pathway; RNF13; Stroke; p62/Nrf2/HO-1
    DOI:  https://doi.org/10.1186/s12964-024-01905-2
  52. PLoS One. 2024 ;19(11): e0313446
    RTA408 alleviates retinal ganglion cells damage in mouse glaucoma by inhibiting excessive autophagy.
    Hongmei Qian, Wei Chen, Guomei Yuan, Man Luo, Li Zhang, Biao Wu, Hanshi Huang, Jiahao Xu, Qiong Wang, Mengyun Li.
      BACKGROUND: Glaucoma, characterized by a high incidence and significant ocular harm, has been elucidated through various mechanisms. Excessive autophagy leading to the loss of retinal ganglion cells (RGCs) is suggested as one potential cause for visual impairment in glaucoma.METHODS: A glaucoma model was established through anterior chamber injection of silicone oil in mice. RTA408 and the positive control tafluprost were administered for intervention. The efficacy was preliminarily assessed by intraocular pressure measurement. HE staining and fluorescent staining were used to assess RGC loss, while fluorescent staining and western blot were employed to evaluate the expression of Nrf2. The role of autophagy in the pathogenesis of glaucoma was investigated by artificially modulating autophagy levels.
    RESULTS: In glaucomatous mice, RTA408 significantly reduces the apoptosis levels of RGCs and decreases RGC loss. Further investigations reveal a notable upregulation of autophagy levels in glaucomatous mice, with RGC loss being associated with autophagy. RTA408 promotes the expression of Nrf2 and downstream antioxidant molecules, enhancing the antioxidant system while downregulating mitochondrial autophagy levels. This reduces RGC apoptosis and loss, demonstrating a protective effect against glaucoma.
    CONCLUSION: Autophagy mediates the occurrence of glaucoma in mice, promoting RGC apoptosis. RTA408 alleviates RGCs damage by inhibiting excessive autophagy in the context of glaucoma.
    DOI:  https://doi.org/10.1371/journal.pone.0313446
  53. Free Radic Biol Med. 2024 Nov 12. pii: S0891-5849(24)01052-9. [Epub ahead of print]
    TSPO Exacerbates Sepsis-Induced Cardiac Dysfunction by Inhibiting p62-Mediated Autophagic Flux via the ROS-RIP1/RIP3-Exosome Axis.
    Qiao Guo, Haitang Liao, Shuai Hao, Dongyao Hou, Ruixue Liu, Yunting Zhang, Xinhao Tang, Rui Song, Xuxin Tan, Zhenchun Luo, He Huang, Chenyang Duan.
      Septic cardiomyopathy (SCM) is a critical complication of sepsis, primarily attributed to mitochondrial dysfunction and impaired autophagic flux. This study explores the role of translocator protein (TSPO) in SCM pathogenesis and assesses its potential as a therapeutic target. We identified increased TSPO expression in plasma samples from sepsis patients, with further validation in septic rats and LPS-stimulated H9C2 cardiomyocytes. Elevated TSPO disrupted mitochondrial function, leading to increased reactive oxygen species (ROS) production and activation of the RIP1/RIP3 pathway, which hindered p62-positive autophagosome degradation and promoted inflammation. Moreover, exosome release containing TSPO-positive autophagosomes into plasma may exacerbate systemic inflammation. NADH, identified as a TSPO-binding molecule, restored autophagic flux, improved mitochondrial function, and enhanced cardiac performance and survival in septic rats. These findings suggest that targeting TSPO with NADH could alleviate mitochondrial dysfunction and inflammatory responses in SCM, providing a promising therapeutic strategy for sepsis-induced cardiac injury.
    Keywords:  LC3II/I; RIP 1/RIP 3; TSPO; autophagy flux; cardiomyopathy; exosomes; inflammation; p62; reactive oxygen species (ROS); sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.018
  54. J Nat Med. 2024 Nov 15.
    Dendrobium nobile Lindl. alkaloids protect CCl4-induced acute liver injury via upregulating LAMP1 expression and activating autophagy flux.
    Nan Nan, Yonggang Yang, Xiaolong Fu, Siting Xian, Qin Wu, Jingshan Shi, Shaoyu Zhou.
      Dendrobium nobile Lindl. alkaloids (DNLA) are considered important active ingredients of Dendrobium, which have a variety of pharmacological functions. Recent studies indicate that DNLA has beneficial activity in acute liver injury. However, the specific mechanism by which DNLA produces liver protective effects is stills unclear. This study was designed to determine whether regulation of autophagy is involved in the mode of action of DNLA in liver protection. Using CCl4-induced acute liver injury (ALI) and cell culture models, the molecular mechanism of DNLA-mediated autophagy regulation was studied. The results showed that DNLA significantly improved CCl4-induced liver damage and oxidative stress, which was confirmed in AML-12 cells. DNLA promoted autophagy in cells treated with CCl4, manifested by reduced protein expressions of p62 and LC3-II. Fluorescence imaging showed a decrease in the number of autophagosomes in AML-12 cells transfected with mCherry-GFP-LC3B. In addition, DNLA inhibited lysosomal membrane permeabilization by upregulating lysosomal associated membrane protein-1 (LAMP1), thereby promoting autophagy, preventing CCl4-induced mitochondrial dysfunction, and reducing the production of mitochondrial reactive oxygen species (ROS). While pretreatment of cells with lysosomal inhibitor chloroquine weakened mitochondrial protection elicited by DNLA, overexpression of mitochondrial-targeted SOD2 in AML-12 cells significantly blocked CCl4 induced downregulation of LAMP1, thereby improving lysosome integrity and promoting lysosome dependent autophagy, suggesting that there may exist a bidirectional regulation between mitochondrial ROS and lysosome-autophagy activation. Collectively, these results demonstrated that DNLA can protect the liver injury mediated by dysregulation of lysosome-autophagy process through promoting ROS-lysosome-autophagy axis and improving mitochondrial damage.
    Keywords:   Dendrobium nobile Lindl. alkaloids; Autophagy; CCl4 ; LAMP1; Liver injury; Mitochondrial ROS
    DOI:  https://doi.org/10.1007/s11418-024-01852-9
  55. Cell Death Dis. 2024 Nov 14. 15(11): 827
    Ally or traitor: the dual role of p62 in caspase-2 regulation.
    Pavel I Volik, Alexey V Zamaraev, Aleksandra Y Egorshina, Nikolay V Pervushin, Anastasia A Kapusta, Pyotr A Tyurin-Kuzmin, Anastasia V Lipatova, Thilo Kaehne, Inna N Lavrik, Boris Zhivotovsky, Gelina S Kopeina.
      Caspase-2 is a unique and conserved cysteine protease that is involved in several cellular processes, including different forms of cell death, maintenance of genomic stability, and the response to reactive oxygen species. Despite advances in caspase-2 research in recent years, the mechanisms underlying its activation remain largely unclear. Although caspase-2 is activated in the PIDDosome complex, its processing could occur even in the absence of PIDD1 and/or RAIDD, suggesting the existence of an alternative platform for caspase-2 activation. Here, we show that caspase-2 undergoes ubiquitination and interacts with scaffolding protein p62/sequestosome-1 (SQSTM1) under normal conditions and in response to DNA damage. p62 promotes proteasomal but not autophagic caspase-2 degradation as well as its dimerization and activation that triggers the caspase cascade and, subsequently, cell death. Inhibition of p62 expression attenuates cisplatin-induced caspase-2 processing and apoptosis. Notably, the ZZ domain of p62 is critical for caspase-2 binding, whereas the UBA domain is seemingly required to stabilize the p62-caspase-2 complex. Thus, we have uncovered the dual role of p62 in regulating caspase-2 activity: it can foster the degradation of caspase-2 in the proteasome or facilitate its activation by acting as a scaffold platform.
    DOI:  https://doi.org/10.1038/s41419-024-07230-3
  56. Cell Death Dis. 2024 Nov 15. 15(11): 834
    Amantadine against glioma via ROS-mediated apoptosis and autophagy arrest.
    Yusong Luo, Ruolan Liu, He Zhang, Hongyu Wang, Hang Yin, Guopeng Tian, Bo Wang, Yunji Yan, Zilin Ding, Junqiang Dai, Liang Niu, Guoqiang Yuan, Yawen Pan.
      Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients.
    DOI:  https://doi.org/10.1038/s41419-024-07228-x
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