bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–11–23
forty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. New Insights into the Essentiality of Core Autophagy Factors Revealed by Comprehensive Analysis.
  2. Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
  3. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
  4. SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1.
  5. Non-canonical roles of lysosomes in neurons.
  6. Autophagic failure with age: influence on metabolic disorders and prospects for therapeutic targeting.
  7. Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
  8. Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy.
  9. SH3P2-mediated autophagosomal targeting of the CCZ1-MON1-RABG3e module regulates autophagosome-vacuole fusion in Arabidopsis.
  10. Circadian gating of autophagy: Not a continuous process?
  11. Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
  12. Electroacupuncture regulates neuronal ferroptosis and ferritinophagy through lysosomal-mediated TFEB activation in cerebral ischemia-reperfusion.
  13. Acute liver failure-induced arginine deficiency impairs blood-brain barrier via inhibiting mTORC1-S6K1/4EBP1 pathway and inducing autophagy.
  14. Autophagy inhibition in intestinal stem cells favors enteroendocrine cell differentiation through Stat92E activity.
  15. The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.
  16. Everolimus ameliorates cognitive deficits and synaptic dysfunction in mice with prefrontal cortical ADNP knockdown.
  17. A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
  18. CK2α Regulates Endoplasmic Reticulum Stress-Mediated Mitophagy via the PERK/ATF4/CHOP Pathway in Rotenone-Treated SH-SY5Y Cells.
  19. Beyond the nucleus: the ATM-CHEK2 axis senses mtROS to orchestrate Mitophagy.
  20. Autophagy regulation by phase separation, avidity, and wetting.
  21. Emerging perspectives on the selective autophagy of melanosomes: melanophagy.
  22. Pharmacological Regulation of Mitophagy by Natural Plant Products as a Therapeutic Target for Alzheimer's Disease.
  23. Mitophagy is responsible to ionizing radiation but plays a very limited role in the radiosensitivity of adenocarcinoma cells.
  24. The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.
  25. Macrophages lacking TSC2 have mTORC1-dependent increased GPNMB and ameliorate ventricular dysfunction/remodeling after ischemia-reperfusion.
  26. Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
  27. Mapping the global research landscape of mitophagy in Parkinson's disease: a bibliometric and visualization analysis.
  28. Failure of lysosomal acidification and endomembrane network in neurodegeneration.
  29. Regulation of pexophagy by a novel TBK1-MARCHF7-PXMP4-NBR1 Axis in PEX1-depleted HeLa cells.
  30. Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
  31. DEPTOR regulates nucleus pulposus cell senescence through the mTORC1/S6K1/ATG1 pathway to alleviate intervertebral disk degeneration.
  32. Cell Trafficking Disorders Play an Important Role in the Pathogenesis of Skeletal Dysplasias.
  33. Functional analyses and integrated mechanisms of cellular destruction by L-amino acid oxidase.
  34. Role of Rubicon in Platelets: A Promoter of Thrombosis but Not an Autophagy Repressor.
  35. Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.
  36. The Lysosome Surface is an Unappreciated Hub for Vasopressin V2 Receptor Signaling.
  37. PRDX1 promotes testosterone synthesis and attenuates aging via redox regulation of ATG4B to modulate lipophagy.
  38. Treatment with L-type amino acid transporter 1 inhibitor JPH203 enhances protein synthesis in C2C12 myotubes.
  39. Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration.
  40. Astrocytic Sox9 overexpression in Alzheimer's disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function.
  41. ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth.
  42. TORC2 inactivation promotes heterochromatin formation in rDNA and prolongs viability of quiescent fission yeast cells.
  43. Differential ion selectivity and disease-associated dysfunction of TRPML channels revealed by patient and engineered mutants.
  44. Trimetazidine alleviates heart failure after myocardial infarction by promoting PINK1/parkin-mediated mitophagy and suppressing GPX4-dependent ferroptosis.
  1. J Biochem. 2025 Nov 21. pii: mvaf073. [Epub ahead of print]
    New Insights into the Essentiality of Core Autophagy Factors Revealed by Comprehensive Analysis.
    Waka Kojima, Koji Yamano.
      Autophagy is a conserved degradation process delivering intracellular components to lysosomes or vacuoles. Yeast studies have been pivotal in identifying autophagy-related (ATG) genes and defining the core machinery essential for autophagosome formation. A recent comprehensive analysis that systematically examined all atg mutants in S. cerevisiae under autophagy-inducing conditions revealed that mutants lacking Atg13, Atg8-conjugation, or Atg12-conjugation components retain partial activity in certain autophagy-related pathways, indicating that these core factors are not strictly essential for autophagy in yeast. In this commentary, we summarize how recent findings reshape our understanding of the flexibility in the essentiality of core autophagy factors and discuss the emerging importance of protein interaction-driven feedback in autophagy regulation.
    Keywords:  Atg8; Autophagy; Lysosome; Mitophagy; Vacuole
    DOI:  https://doi.org/10.1093/jb/mvaf073
  2. Mol Biol Cell. 2025 Nov 19. mbcE25050235
    Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
    Hubert Osei Acheampong, Emily Rozich, Zachary Haupt, Charlee Tokarz, Mousumee Khan, Zahraa A Ghosn, Ryan Insolera.
      The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate the Drosophila autophagy adaptor gene Kenny, a homolog of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homolog of OPTN in flies, and a mediator of neuronal mitophagy in vivo.
    DOI:  https://doi.org/10.1091/mbc.E25-05-0235
  3. bioRxiv. 2025 Oct 03. pii: 2025.10.01.679861. [Epub ahead of print]
    Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
    Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.
      The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, while aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established several regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, a liver-specific mouse model that disconnects mTORC1 activation from AKT-mediated TSC2 phosphorylation is employed. This genetic mouse model demonstrates that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, dietary protein is critical and dictates the insulin-responsiveness of hepatic mTORC1 signaling. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity associated with the phenotypes of type-2 diabetes, including hyperinsulinemia, systemic insulin resistance, and hyperglycemia, and blocking hepatic AKT-TSC-mTORC1 signaling did not prevent these metabolic impairments. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.
    DOI:  https://doi.org/10.1101/2025.10.01.679861
  4. FEBS Open Bio. 2025 Nov 20.
    SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1.
    Isabell Lehmkuhl, Khawar Amin, Lydia Gabriel, Nils Hampel, Afshin Iram, Julia Hesse, Constanze Wiek, Jasmin Thuy Vy Nguyen, Helmut Hanenberg, Jürgen Scheller, M Reza Ahmadian, Björn Stork, Doreen M Floss, Roland P Piekorz.
      The sirtuin SIRT4 has been implicated in the control of autophagy and mitochondrial quality control via mitophagy. However, the role of SIRT4 in regulating autophagy/mitophagy induced by different stressors is unclear. Here, we show that cells expressing SIRT4(H161Y), a catalytically inactive, dominant-negative mutant of SIRT4, fail to upregulate LC3B-II. These cells also exhibit a reduced autophagic flux upon treatment with different inducers of mitophagy/autophagy, that is, CoCl2-triggered pseudohypoxia, CCCP (carbonyl cyanide 3-chlorophenylhydrazone)/oligomycin-mediated respiratory chain inhibition, or rapamycin treatment. Interestingly, SIRT4(H161Y) expression upregulated protein levels of HDAC6, which is involved in mitochondrial trafficking and autophagosome-lysosome fusion, and inhibited the conversion of OPA1-L to OPA1-S, which is associated with increased mitochondrial fusion and decreased mitophagy. Both HDAC6 and OPA1 are SIRT4 interactors. However, the pharmacological inhibition of HDAC6 using Tubacin or of OPA1 using MYLS22 did not restore the stress-induced upregulation of LC3B-II levels upon autophagy/mitophagy treatment in SIRT4(H161Y)-expressing cells. Remarkably, inhibition of autophagosome-lysosome fusion and thus disruption of late autophagic flux by BafA1 treatment also failed to restore LC3B-II levels upon autophagy/mitophagy treatment, suggesting an inhibitory effect of SIRT4(H161Y) on the initiation/early phase of autophagy. Consistent with this, we demonstrate that SIRT4(H161Y) promotes the phosphorylation of ULK1 at S638 and S758 (mTORC1 targets), both of which mediate an important inhibitory regulation of autophagy initiation. Thus, our data suggest a positive regulatory function of SIRT4 in the ULK1-dependent early regulation/initiation of stress-induced autophagic flux, presumably via modulation of AMPK/mTORC1 signaling.
    Keywords:  HDAC6; LC3; OPA1; SIRT4; ULK1; autophagy
    DOI:  https://doi.org/10.1002/2211-5463.70164
  5. Trends Neurosci. 2025 Nov 18. pii: S0166-2236(25)00222-X. [Epub ahead of print]
    Non-canonical roles of lysosomes in neurons.
    Jonathan I Spencer, Yulia Sudarikova, Michael J Devine.
      Neurons are highly polarised and compartmentalised cells with organelles that are specialised to support their spatial and functional demands. This includes lysosomes, which are single-membrane-bound organelles enveloping acidic contents enriched with hydrolytic enzymes. While classically thought to be localised at the soma where they degrade waste, lysosomes have a range of dynamic nondegradative functions throughout neurons. Here, we review lysosomal dynamics and non-canonical functions in neurons, including axonal mRNA transport, mammalian target of rapamycin (mTOR) and Ca2+ signalling, neuronal remodelling, and interorganellar contact sites. We synthesise work across a range of model systems and species, providing insights from neurological diseases, where previous lysosomal research has focussed on proteostatic failure. This perspective highlights the need to better define lysosomal heterogeneity, compartmentalisation and specialisation in neurons.
    Keywords:  autophagy; neurodegeneration; neuronal plasticity; synapse; trafficking
    DOI:  https://doi.org/10.1016/j.tins.2025.10.009
  6. Expert Opin Ther Targets. 2025 Nov 16. 1-10
    Autophagic failure with age: influence on metabolic disorders and prospects for therapeutic targeting.
    Emma Brand, Mbalenhle Ntuli, Benjamin Loos.
       INTRODUCTION: Autophagy, from Greek auto, meaning self and phagein to eat, is a highly conserved cellular pathway responsible for the degradation and recycling of long-lived proteins. A functional autophagy pathway, characterized by cell- and tissue-specific basal autophagy activity, is crucial for the cell's successful response to aging and the mitigation of age-related pathologies. However, comprehensive understanding of underlying mechanisms and spatiotemporal profiling of autophagy flux across tissues remain largely elusive.
    AREAS COVERED: Here, we attempt to dissect how to better discern key metrics that may inform autophagy failure. By reporting evidence for tissue-inherent autophagy activities, their flux responses in magnitude and capacity, we provide a new perspective on existing data of species-specific autophagy in age. By evaluating the connection between autophagy activity in peripheral blood mononuclear cells (PBMCs) relative to tissue associated autophagy failure, new concepts are provided that may assist in accelerating targeted development of therapeutic interventions.
    EXPERT OPINION: Despite major progress in understanding the molecular mechanisms of autophagy in aging, knowledge gaps remain in standardizing methods to accurately monitor tissue-specific autophagy activity and cargo clearance. Building comprehensive databases, integrating multi-scale imaging, multi-omics, and AI-driven analyses will be essential for developing effective autophagy-targeted therapies for age-related diseases.
    Keywords:  Autophagy activity; age; autophagy pathway intermediates; flux; neurodegeneration
    DOI:  https://doi.org/10.1080/14728222.2025.2584012
  7. Exp Physiol. 2025 Nov 19.
    Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
    Anastasiya Kuznyetsova, David A Hood.
      Skeletal muscle plays an important role in whole-body health, quality of life and regulation of metabolism. The maintenance of a healthy mitochondrial pool is imperative for the preservation of skeletal muscle quality and is mediated through mitochondrial quality control consisting of mitochondrial turnover mediated by a balance between organelle synthesis and degradation. The selective tagging and removal of dysfunctional mitochondria is essential for maintaining mitochondrial quality control and is termed mitophagy. The mechanisms of the initial stages of mitophagy involving the recognition and tagging of mitochondria within skeletal muscle are well established, but our understanding of the terminal step involving organelle degradation mediated via lysosomes is in its infancy. An assessment of the proteolytic functions to facilitate the removal and breakdown of dysfunctional mitochondria is crucial for our understanding of the mechanisms of mitophagy, which is essential for maintaining skeletal muscle health. The aim of this review is to address the current knowledge surrounding mitophagy and lysosomal function, alongside distinct physiological conditions, such as ageing, exercise and disuse, that have varying effects on mitophagy and lysosomal adaptations within skeletal muscle.
    Keywords:  Parkin; adaptation; lysosomes; mitophagy; skeletal muscle; transcription factor EB
    DOI:  https://doi.org/10.1113/EP093041
  8. Autophagy Rep. 2025 ;4(1): 2580781
    Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy.
    Byunghyun Ahn, Wenzhe Chen, Wenbiao Shi, Ruben Shrestha, Fenghua Hu, Hening Lin.
      Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation essential for cellular proteostasis. CMA is activated during cellular stress, such as starvation, and involves the chaperone protein HSC70 (HSPA8) recognizing substrates containing KFERQ-like motifs. However, the regulatory mechanisms governing CMA activation remain poorly understood. Here, we demonstrate that the NAD+ -dependent deacetylase SIRT2 promotes CMA activation by deacetylating HSC70 at lysine 557 (K557). Our findings reveal that SIRT2 activity is upregulated during starvation, enhancing its interaction with HSC70 and facilitating the deacetylation of K557. Deacetylation of HSC70 at K557 increases its binding affinity to CMA substrates, thereby promoting their lysosomal degradation. Mutation of K557 to a deacetylation-mimetic arginine (K557R) enhances CMA activity under both nutrient-rich and starvation conditions, while the acetylation-mimetic glutamine mutant (K557Q) impairs substrate binding and CMA activation. Furthermore, the inhibition or knockdown of SIRT2 reduces CMA activity, which is rescued by HSC70 K557R expression. These findings identify SIRT2-mediated deacetylation of HSC70 as a regulatory mechanism for CMA activation during nutrient deprivation and highlight the role of protein lysine acetylation in proteostasis. This study provides insights into the interplay between SIRT2, HSC70, and CMA, with potential implications for diseases linked to proteostasis dysregulation, including neurodegenerative disorders and cancer.
    Keywords:  Chaperone-mediated autophagy; HSC70; KFERQ motif; SIRT2; amino acids starvation; deacetylation; heat shock chaperones; lysosomes; protein degradation; sirtuin
    DOI:  https://doi.org/10.1080/27694127.2025.2580781
  9. Autophagy. 2025 Nov 19.
    SH3P2-mediated autophagosomal targeting of the CCZ1-MON1-RABG3e module regulates autophagosome-vacuole fusion in Arabidopsis.
    Xiaohui Zheng, Xiaotong Zhan, Shufei Tang, Yanbin Li, Hai Zhang, Qing Qi, Jiayang Gao, Congxian Wu, Zhifei Fu, Wilson Chun Yu Lau, Takashi Ueda, Liwen Jiang, Yong Cui.
      Macroautophagy/autophagy is a highly conserved pathway responsible for the bulk degradation of cytoplasmic material through the formation of a double-membrane structure known as the autophagosome. However, the precise mechanisms governing the transport of autophagosomes to the vacuole for degradation in plants remain largely elusive. There exists an ongoing debate about whether RAB7, a key regulatory protein, is involved in the plant autophagy pathway. In this study, we demonstrate that upon autophagy induction by BTH treatment, RABG3e, a member of the RAB7 family, exhibits a partial localization with late-stage autophagosomes in Arabidopsis root cells, and its dysfunction leads to the accumulation of enlarged multilayered autophagosomes and a significant reduction in autophagic flux. We also showed that RABG3e is recruited to autophagosomes by its guanine nucleotide exchange factor (GEF) complex, MON1-CCZ1, which is targeted through the interaction between CCZ1 and SH3P2 (SH3 DOMAIN-CONTAINING PROTEIN 2), a plant-specific autophagy regulator. Subsequently, RABG3e recruits downstream effectors such as VPS39, which in turn promotes the recruitment of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins, including SYP21, VTI12, SYP51, and VAMP711, that are essential for the fusion process. Arabidopsis mutants with dysfunction in the autophagosome-vacuole fusion process exhibit accelerated senescence and increased sensitivity to nitrogen starvation. Collectively, our findings provide new insights into the regulation of autophagosome-vacuole fusion in Arabidopsis, highlighting the essential roles of SH3P2-dependent targeting of the CCZ1-MON1-RABG3e module to late-stage autophagosomes as well as RABG3e effectors and a unique SNARE complex.
    Keywords:  Arabidopsis; CCZ1-MON1; RABG3e; SH3P2; Vacuole; plant autophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593138
  10. Plant Sci. 2025 Nov 16. pii: S0168-9452(25)00499-6. [Epub ahead of print]363 112881
    Circadian gating of autophagy: Not a continuous process?
    Laha Supriya, Deepika Dake, Padmaja Gudipalli, Mehanathan Muthamilarasan.
      Autophagy has long been considered or viewed as a stress-induced or constitutive cellular process, supporting homeostasis through the degradation and recycling of damaged components. However, emerging evidence challenges this traditional view, revealing that autophagy is not continuously active in plants but follows a time-gated phenomenon orchestrated by the plant's internal clock. Recent studies show that core circadian regulators, including TOC1, PRRs, COR and LUX, repress autophagy-related genes (ATGs) expression during daytime (after zeitgeber time 0 (ZT0) to before ZT15), actively gating the process and becoming activated post-ZT15, when cellular sugar levels decline, correlated with SnRK1 activation. This circadian gating aligns autophagic flux with predictable metabolic transitions, positioning it as an anticipatory mechanism. In this correspondence article, we combine molecular and physiological data that collectively support a paradigm shift: autophagy in plants operates as a clock-directed, non-continuous process. Understanding this rhythmic coordination offers new strategies to leverage circadian-autophagy coupling for engineering spatiotemporal stress resilience in crops.
    Keywords:  ATG genes; Autophagy; Circadian rhythm; Clock genes; Spatiotemporal control; Stress tolerance; TOR-SnRK1 signaling
    DOI:  https://doi.org/10.1016/j.plantsci.2025.112881
  11. J Cell Biol. 2026 Jan 05. pii: e202503028. [Epub ahead of print]225(1):
    Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
    Shuai Liu, Lina Ma, Ruiqi Lv, Liangting Guo, Xing Pan, Shufan Hu, Shan Li.
      Mitophagy transports mitochondria to lysosomes for degradation to maintain energy homeostasis, inflammation, and immunity. Here, we identify CipB, a type III secretion system (T3SS) effector from Chromobacterium violaceum, as a novel exogenous mitophagy receptor. CipB targets mitochondria by the mitochondrial protein TUFM and recruits autophagosomes via its LC3-interacting region (LIR) motifs. This process initiates the mitophagy-TFEB axis, triggering TFEB nuclear translocation and suppression of proinflammatory cytokines, thereby promoting bacterial survival and pathogenesis. CipB represents a conserved family of T3SS effectors employed by diverse pathogens to manipulate host mitophagy. Using a mouse model, CipB's mitophagy receptor function is critical for C. violaceum colonization in the liver and spleen, underscoring its role in bacterial virulence. This study reveals a novel mechanism by which bacterial pathogens exploit host mitophagy to suppress immune responses, defining CipB as a paradigm for exogenous mitophagy receptors. These findings advance our understanding of pathogen-host interactions and highlight the mitophagy-TFEB axis as a potential signaling pathway against bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202503028
  12. J Cereb Blood Flow Metab. 2025 Nov 21. 271678X251399016
    Electroacupuncture regulates neuronal ferroptosis and ferritinophagy through lysosomal-mediated TFEB activation in cerebral ischemia-reperfusion.
    Bin Tang, Xifa Xu, Wenting Zhao, Qingchen Zhou, Guangzhong Du, Huanyuan Wang.
      Ferroptosis is an iron-dependent form of oxidative cell death involved in the pathogenesis of ischemic stroke. Electroacupuncture (EA) is an effective therapeutic intervention for ischemic stroke with antioxidant effects. However, the potential connection between EA and ferroptosis, as well as the underlying mechanisms, are largely unexplored. Here, we explored the vital role of EA in ferroptosis-mediated ischemic insult and the underlying mechanisms in the male rats with middle cerebral artery occlusion/reperfusion (MCAO/R). To determine whether preserved TFEB activity is responsible for EA-mediated inhibition of ferroptosis and lysosomal dysfunction in CIR, we used shRNA-mediated knockdown of TFEB in neurons. The results showed that EA scavenged lipid peroxidation, alleviated neuronal ferroptosis, and ferritinophagy in cerebral ischemia-reperfusion (CIR). EA also suppressed lysosomal dysfunction and preserved transcription factor EB (TFEB) activation, which was at least partially mediated through mTORC1 (mechanistic target of rapamycin kinase complex 1). The loss of TFEB counteracted EA-mediated inhibition of ferroptosis and lysosomal dysfunction in CIR. Furthermore, EA significantly alleviated CIR-induced neuronal injury in a TFEB-dependent manner. Collectively, EA can effectively suppress ferroptosis and ferritinophagy, induce TFEB-dependent lysosomal biogenesis, and inhibit lysosomal membrane permeabilization (LMP)-mediated lysosome iron efflux into a malignant circuit in CIR.
    Keywords:  Cerebral ischemia-reperfusion injury; electroacupuncture; ferroptosis; lysosome; transcription factor EB
    DOI:  https://doi.org/10.1177/0271678X251399016
  13. Cell Death Dis. 2025 Nov 17. 16(1): 842
    Acute liver failure-induced arginine deficiency impairs blood-brain barrier via inhibiting mTORC1-S6K1/4EBP1 pathway and inducing autophagy.
    Hanyu Yang, Weimin Kong, Ling Jiang, Liang Zhu, Xun Wang, Lu Yang, Liqiang Qian, Zijun Xu, Chenyang Zhang, Xiaodong Liu, Li Liu.
      Blood-brain barrier (BBB) impairment plays a crucial role in the development of hepatic encephalopathy. Our previous work demonstrated that hepatic ischemia-reperfusion-induced acute liver failure (ALF) impairs the BBB by releasing arginase, but the underlying mechanism remains unclear. In this study, we discovered that ALF-induced arginase accumulation leads to arginine (Arg) deficiency, causing BBB cells to arrest in G1 phase. This arrest was associated with decreased expression of key cell cycle regulatory proteins, activation of autophagy, and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Silencing mTORC1 downstream protein p70 ribosomal protein S6 kinase 1 (S6K1) or eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) showed similar effects as Arg deficiency, while activating the mTORC1 pathway attenuated arginase-induced cell cycle delay. Furthermore, inhibition of autophagy with 3-methyladenine or silencing Beclin-1 partially reversed the arginase-induced effects. These in vitro findings were corroborated in rat models of ALF induced by thioacetamide or acetaminophen, as well as in rats treated with arginase, all of which exhibited elevated plasma arginase activity, reduced Arg levels, increased BBB permeability, and suppressed BBB cell proliferation. These changes were accompanied by alterations in markers related to cell cycles, mTORC1 signaling, and autophagy, which were reversible upon Arg supplementation. In summary, our research reveals that ALF-induced BBB damage is driven by Arg deprivation due to arginase release, leading to G1 phase arrest through mTORC1 pathway inhibition and autophagy induction, which provides new insights into the prevention and treatment of ALF-induced BBB damage and hepatic encephalopathy.
    DOI:  https://doi.org/10.1038/s41419-025-08152-4
  14. Dis Model Mech. 2025 Nov 20. pii: dmm.052214. [Epub ahead of print]
    Autophagy inhibition in intestinal stem cells favors enteroendocrine cell differentiation through Stat92E activity.
    Camille Lacarrière-Keïta, Sonya Nassari, Jessica Boutet, Véronique Gaudreault, Steve Jean.
      Because the intestinal epithelium is exposed to various stressors, dysregulation of essential mechanisms that maintain gut homeostasis, such as autophagy, has been linked to inflammatory bowel pathologies. In Drosophila melanogaster, inhibition of autophagy specifically in adult intestinal stem cells (ISCs) affects their proportions differently during aging. Proper intestinal renewal requires a balance between ISC proliferation and differentiation. Here, we show that in adult ISCs, loss of core autophagy genes and regulators of autophagosome-lysosome fusion increases the enteroendocrine cell population and enhances the transcriptional activity of Stat92E. Functional experiments involving cell fate regulators of enteroendocrine or enterocyte differentiation and proliferation suggest that dysfunctional autophagy in adult ISCs enhances Stat92E activity downstream of Hop/JAK kinase. Finally, lineage-tracing analyses confirm that autophagy inhibition promotes enteroendocrine cell differentiation. Thus, our data demonstrate that, under homeostatic conditions, basal autophagy limits enteroendocrine cell differentiation by regulating Stat92E activity, which can be counteracted by the transcription factor Scute.
    Keywords:   Drosophila ; Autophagy; Cell fate; Differentiation; Intestinal stem cell; JAK-STAT; Scute; Stat92E
    DOI:  https://doi.org/10.1242/dmm.052214
  15. Front Mol Biosci. 2025 ;12 1673249
    The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.
    Marius Wilhelm Baeken, Fazilet Bekbulat, Hagen Körschgen, Albrecht Martin Clement, Christian Behl.
      Gamma-aminobutyric acid receptor-associated protein (GABARAP) is a multifunctional member of the autophagy-related (ATG8) protein family, playing key roles in two distinct cellular pathways: macroautophagy and plasma membrane protein trafficking. In the context of autophagy, GABARAP modulates cargo recognition and supports the maturation and fusion of autophagosomes with lysosomes, a critical step in intracellular clearance and proteostasis. Separately, GABARAP also regulates vesicular receptor protein transport from the Golgi apparatus to the plasma membrane, contributing to proper surface localization and receptor recycling. Both tasks are especially vital for neurons, where protein turnover and receptor localization are tightly linked to synaptic plasticity and neuroprotection. We recently identified a direct interaction between GABARAP and the sigma-1 receptor (σ1R), an ER-resident receptor involved in diverse cellular stress responses, mitochondrial function, and protein homeostasis. Our findings suggest that σ1R acts as an upstream regulatory hub, influencing GABARAP's functional commitment to either membrane trafficking or autophagy. Specifically, we hypothesize that ligand-dependent σ1R activation promotes GABARAP's involvement in macroautophagy at the expense of its role in membrane transport. This regulatory switch may underline part of the neuroprotective effects observed with σ1R agonists in neurodegenerative disease models, where enhanced autophagy is often beneficial. Overall, we discuss the emerging molecular crosstalk between σ1R and GABARAP, its potential impact on neuronal homeostasis, and how σ1R's pharmacological modulation might be leveraged to bias GABARAP function toward autophagy in diseases such as amyotrophic lateral sclerosis, Huntington's, Parkinson's, and Alzheimer's disease.
    Keywords:  GABARAP; GABAa receptor; LIR; autophagy; sigma-1 receptor
    DOI:  https://doi.org/10.3389/fmolb.2025.1673249
  16. Neurosci Lett. 2025 Nov 18. pii: S0304-3940(25)00349-0. [Epub ahead of print] 138460
    Everolimus ameliorates cognitive deficits and synaptic dysfunction in mice with prefrontal cortical ADNP knockdown.
    Yu Xiang, Zeyu Zhang, Yunrui Jiang, Hongen Wei.
      Activity-dependent neuroprotective protein (ADNP), a major risk gene for autism spectrum disorder (ASD) and intellectual disability (ID), is critical for brain development and cognition. Among its regulated processes, autophagy is notably affected, with mTORC1 overactivation acting as a negative regulator and frequently reported in ASD. Rapamycin can rescue ASD-related behaviors, and everolimus (EVR), an optimized derivative, is widely applied in clinical practice. However, its role in ADNP-related pathology remains unknown. Here, we established a prefrontal cortex (PFC) ADNP knockdown (KD) mouse model to examine behavioral and molecular consequences, and whether EVR provides benefit. We found that ADNP KD resulted in mTORC1 pathway activation, autophagy impairment, learning and memory deficits, and anxiety-like behaviors, concurrent with dysregulation of microtubule and synaptic proteins. Daily intraperitoneal EVR (5 mg/kg) can effectively alleviate the behavioral and molecular phenotypes caused by ADNP deficiency in the PFC, thereby establishing a strong rationale for targeting the mTOR pathway in treating ADNP-related cognitive impairments.
    Keywords:  ADNP; Everolimus; Microtubules; Synapses; mTOR
    DOI:  https://doi.org/10.1016/j.neulet.2025.138460
  17. EMBO J. 2025 Nov 20.
    A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.
    Keywords:  Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response
    DOI:  https://doi.org/10.1038/s44318-025-00604-z
  18. Mol Neurobiol. 2025 Nov 19. 63(1): 69
    CK2α Regulates Endoplasmic Reticulum Stress-Mediated Mitophagy via the PERK/ATF4/CHOP Pathway in Rotenone-Treated SH-SY5Y Cells.
    Kyung Mi Lim, Jungwook Hwang, Hyun Chul Koh.
      Mitophagy refers to selective mitochondrial autophagy to remove damaged mitochondria and plays a critical role in maintaining mitochondria homeostasis. Casein kinase 2α (CK2α) is involved in mitophagy regulation in dopaminergic neurons. Endoplasmic reticulum (ER) stress releases calcium into mitochondria, leading to mitochondrial dysfunction and contributing to various diseases. However, it is not clear whether CK2α regulates ER-mediated mitochondrial dysfunction and mitophagy in response to ER stress. Therefore, we investigated the effects of ER stress on mitophagy during rotenone-induced ER stress and mitochondrial damage in SH-SY5Y cells and elucidated the role of CK2α in this process. Rotenone increased the expression of P-PERK and P-IRE1α, thereby activating ER stress sensors. CK2α inhibition suppressed PERK and IRE1α activation and their downstream signaling components (eIF2α, ATF4, CHOP and XBP1s). Furthermore, CK2α inhibition enhanced PINK1/Parkin-mediated mitophagy by increasing PINK1 and Parkin translocation to mitochondria in addition to inducing LC3II expression. These results suggest that CK2α regulates PINK/Parkin-dependent mitophagy in rotenone-treated cells. Interestingly, treatment of cells with the PERK inhibitor GSK2606414 also resulted in increased PINK1/Parkin-mediated mitophagy. Moreover, CK2α inhibition reduced rotenone-induced apoptosis by modulating PERK signaling. These findings suggest that CK2α plays a key role in regulating the ER stress response and PERK-dependent PINK1/Parkin-mediated mitophagy in our rotenone-induced apoptosis model. This study highlights the therapeutic potential of CK2α signal regulation for treating diseases driven by ER stress and mitochondrial dysfunction, offering a promising avenue for future research.
    Keywords:  Casein kinase 2α; ER stress; Mitophagy; PERK/ATF4/CHOP pathway; PINK/Parkin; Rotenone
    DOI:  https://doi.org/10.1007/s12035-025-05441-z
  19. Autophagy. 2025 Nov 19.
    Beyond the nucleus: the ATM-CHEK2 axis senses mtROS to orchestrate Mitophagy.
    Qi-Qiang Guo, Xiao-Yu Song, Liu Cao.
      Mitochondrial reactive oxygen species (mtROS) are typically viewed as harmful byproducts of stress. However, our recent study establishes their fundamental role as essential signaling molecules that activate a protective adaptive response. We discovered that mtROS serve as the specific trigger to activate the ATM-CHEK2/CHK2 DNA damage response pathway, which in turn coordinates the key steps of PINK1-PRKN/Parkin-dependent mitophagy. Upon activation by mtROS, CHEK2 phosphorylates ATAD3A to initiate PINK1 import arrest, OPTN to enhance cargo recognition, and BECN1 (beclin 1) to promote autophagosome formation. This work reveals a novel mtROS-driven signaling cascade, expanding the function of the ATM-CHEK2 pathway beyond the nucleus and positioning it as a central integrator of cellular homeostasis by responding to both genomic and mitochondrial stress.
    Keywords:  Dna damage response pathway; OPTN; PINK1; mitophagy; mtROS
    DOI:  https://doi.org/10.1080/15548627.2025.2592883
  20. Trends Biochem Sci. 2025 Nov 19. pii: S0968-0004(25)00244-0. [Epub ahead of print]
    Autophagy regulation by phase separation, avidity, and wetting.
    Riccardo Babic, Joachim Brenneisen, Florian Wilfling, Claudine Kraft.
      Autophagy enables cells to selectively degrade a wide range of macromolecules, and how this process achieves spatial precision within the densely packed cytosol is an active area of investigation. Recent advances suggest that phase separation provides a crucial organizational framework that converts autophagy into a spatiotemporally coordinated and self-organizing process. Biomolecular condensates formed by phase separation can create high-avidity binding platforms between autophagy receptors, scaffold proteins, and the cargo that stabilize transient molecular contacts. The formation of such condensates specifies the cargo and initiates autophagosome formation at defined cellular locations. Simultaneously, physical properties such as wetting govern how condensates interact with membranes, and thus influence engulfment efficiency. Viewing autophagy through the lens of condensate physics not only explains its molecular specificity but also highlights new therapeutic opportunities.
    Keywords:  autophagy; autophagy-based therapeutics; avidity; biomolecular condensates; phase separation; wetting
    DOI:  https://doi.org/10.1016/j.tibs.2025.10.003
  21. Exp Mol Med. 2025 Nov 14.
    Emerging perspectives on the selective autophagy of melanosomes: melanophagy.
    Na Yeon Park, Seong Hyun Kim, Doo Sin Jo, Dong-Hyung Cho.
      Melanosomes are highly specialized organelles responsible for melanin synthesis, storage and transport in melanocytes, playing a central role in pigmentation and skin homeostasis. Although melanosome biogenesis and trafficking have been well characterized, emerging evidence emphasizes the importance of melanosome degradation in regulating pigment levels. Among the degradation pathways, melanophagy-a selective form of autophagy targeting melanosomes-has recently emerged as an important mechanism for the turnover of damaged, immature, or excess melanosomes. Here we highlight current insights into melanophagy mechanisms, including molecular regulators and signaling pathways. We also discuss the potential of modulating melanophagy as a novel cosmetic or therapeutic approach for managing hyperpigmentation, offering an alternative to traditional strategies focused solely on inhibiting melanin synthesis. By emphasizing the role of organelle clearance, melanophagy provides a new paradigm in the regulation of skin pigmentation.
    DOI:  https://doi.org/10.1038/s12276-025-01581-3
  22. Phytother Res. 2025 Nov 21.
    Pharmacological Regulation of Mitophagy by Natural Plant Products as a Therapeutic Target for Alzheimer's Disease.
    Simai Shao, Hao Lu, Runru Zu, Yuanzhao Chen, Zhichuan Peng, Quekun Peng, Huifen Ma, Yiran Sun.
      Alzheimer's disease (AD), a prevalent senile dementia, is characterized by the progressive decline in cognitive function, accumulation of tau tangles and Aβ plaques. Despite significant research efforts in the field of AD, effective therapeutic drugs for its prevention and treatment remain elusive. Consequently, a more comprehensive understanding of the molecular mechanisms underlying the pathological processes of AD is crucial for novel therapeutic strategies. Mitophagy, the selective degradation of mitochondria through autophagy, is an essential mechanism for maintaining mitochondrial homeostasis in terms of both quantity and quality. Mitophagy plays a crucial role in numerous cellular processes, including inflammation, differentiation, and apoptosis. Recent studies have increasingly demonstrated that mitophagy is extensively characterized in AD and may represent a novel therapeutic strategy for its treatment. Notably, a number of natural plant products (NPPs) have been demonstrated to modulate mitophagy and intervene in the pathological process of AD. For instance, NPPs such as urolithin A and β-asarone have been reported to enhance mitophagy by activating the PINK1/Parkin pathway, thereby alleviating Aβ-induced neurotoxicity. The distinctive multi-target properties and favorable safety profiles of NPPs endow them with significant research potential and developmental value, establishing them as a vital resource for novel drug discovery. This review explores the mechanistic hypotheses linking mitophagy to AD pathology and provides a systematic overview of recent advances in representative NPPs that regulate mitophagy to alleviate AD-related impairments, offering new perspectives for the development of therapeutic strategies against AD.
    Keywords:  Alzheimer's disease; Mitophagy; mitochondria; natural plant products
    DOI:  https://doi.org/10.1002/ptr.70131
  23. Hum Cell. 2025 Nov 21. 39(1): 12
    Mitophagy is responsible to ionizing radiation but plays a very limited role in the radiosensitivity of adenocarcinoma cells.
    Chen Yan, Kai Huang, Yong Xu, Wei-Hang Lu, Jing Cai, Tao-Sheng Li.
      Radioresistance of adenocarcinoma cells limits the efficiency of radiotherapy. In addition to the cell nucleus, ionizing radiation (IR) also induces damage to the mitochondria. Mitophagy, a selective degradation of impaired mitochondria via autophagy, has been found to respond to IR, but its role in the radiosensitivity of adenocarcinoma cells remains unclear. Using several different adenocarcinoma cell lines, we confirmed that exposing the adenocarcinoma cells to 5 Gy X-ray enhanced the expression of some mitophagy receptors and increased mitophagy activity. However, pharmacological inhibition of mitophagy by mdivi-1 did not significantly change the radiosensitivity of HCT116 and A549 cells. Similarly, molecular targeting inhibition of mitophagy by BNIP3L knockdown in HCT116 and A549 cells that showed significant IR-induced BNIP3L up-regulation did also not significantly affect the radiosensitivity of adenocarcinoma cells, although the IR-induced enhancement of mitophagy activity was effectively suppressed. According to our data, mitophagy is responsible to IR but plays a very limited role in the radiosensitivity of adenocarcinoma cells. Further in vivo studies are warranted to elucidate the radiosensitizing effect of targeting mitophagy on malignant tumors.
    Keywords:  Adenocarcinoma; Autophagy; BNIP3L; Mitophagy; Radiotherapy
    DOI:  https://doi.org/10.1007/s13577-025-01328-2
  24. Prog Neurobiol. 2025 Nov 16. pii: S0301-0082(25)00145-5. [Epub ahead of print]255 102854
    The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.
    Courtney Lane-Donovan, Mercedes Paredes, Aimee W Kao.
      In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs-development and aging-that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (GBA: Gaucher's disease and Parkinson's disease), progranulin (GRN: neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (TSC1: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as "Lysosomal Clearance Disorders."
    Keywords:  Alzheimer’s disease; Dementia; Epilepsy; Gaucher’s disease; Lysosomal storage disease; Neurodegeneration; Parkinson’s disease; Proteostasis; Seizure; Selective neuronal vulnerability
    DOI:  https://doi.org/10.1016/j.pneurobio.2025.102854
  25. Sci Rep. 2025 Nov 19. 15(1): 40891
    Macrophages lacking TSC2 have mTORC1-dependent increased GPNMB and ameliorate ventricular dysfunction/remodeling after ischemia-reperfusion.
    Mohammad Keykhaei, Navid Koleini, Mariam Meddeb, David J Polhemus, Masih Tajdini, Malihe Rezaee, Qiao Huang, Tegbir Panesar, Mark J Ranek, Luigi Adamo, David A Kass.
      Macrophages (MΦ) modulate myocardial inflammation and repair after ischemia-reperfusion (I/R) injury. The mechanistic target of rapamycin (mTOR) regulates MΦ phenotype and functionality, but studies conflict regarding its pro- or anti-inflammatory role. To test this, myeloid TSC2 depleted (MΦTSC2-/-) mice were generated by crossing Lys2Cre with TSC2flx/flx. In vitro, bone marrow-derived MΦTSC2-/- vs. control MΦ had greater mTORC1 and less mTORC2 activity coupled with differential responses to pro- or anti-inflammatory ligands. These disparities were eliminated by inhibiting mTORC1 with rapamycin. MΦTSC2-/- mice had substantially less cardiac dysfunction and ventricular remodeling after I/R, with reduced lung edema and activation of stress/pro fibrotic genes. These differences were eliminated by treating mice with rapamycin, supporting mTORC1 dependence. Post I/R MΦTSC2-/- myocardium had fewer pro-inflammatory (CCR2+MHC-IIhi) MΦ, LY6C+ monocytes, LY6G + neutrophils, and CD8+ T cells at 5-days post-I/R, and fewer CCR2+ but more CCR2- MΦ 2-wks after I/R. Synthesis of glycoprotein nonmetastatic melanoma protein B (GPNMB), a MΦ secreted anti-inflammatory protein was greater in MΦTSC2-/- macrophages and myocardium after I/R in an mTORC1 dependent manner. Thus, constitutive mTORC1 activation in MΦ depresses pro-inflammatory cell infiltration, increases GPNMB protein expression, and preserves heart function following I/R. This reveals beneficial effects of a MΦ-dependent mTORC1-GPNMB cascade on the post I/R heart.
    Keywords:  Heart; Innate immunity; Ischemia; Mammalian target of rapamycin; Monocyte; Tuberous sclerosis
    DOI:  https://doi.org/10.1038/s41598-025-24699-w
  26. Nat Commun. 2025 Nov 18. 16(1): 10109
    Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice.
    Zhongxin Han, Siyi Xiong, Ke Zeng, Zilong Xiao, Liying Zhang, Yufen Zhang, Jiaying Guo, Wenqiang Peng, Yingchao Xie, Weiwei Liu, Xiao Yu.
      Precise regulation of type I interferon signaling is crucial for effective immune defense against infectious diseases. However, the molecular mechanisms governing this pathway are not fully understood. Here, we show a function for palmitoylation in enhancing anti-malarial immune responses. Our findings reveal that ZDHHC9 enhances the type I interferon signaling by palmitoylating TBK1 at cysteine 292. Following infection with Plasmodium yoelii N67, the delicate balance between palmitoylation and depalmitoylation of TBK1 is disrupted. Specifically, upregulation of APT2 promotes persistent depalmitoylation of TBK1 and triggers its selective autophagic degradation via K48-linked polyubiquitination at lysine 251/372 by E3 ligase TRIM27. This process acts as a recognition signal for the cargo receptor NDP52, resulting in inhibition of the type I interferon pathway. Notably, inhibition of APT2 using ML349 elevates type I interferon levels and improves survival rates against N67 infection. Here, we show that targeting APT2-mediated TBK1 depalmitoylation is a potential therapeutic strategy for malaria and may also be applicable to other diseases driven by dysregulated type I interferon signaling.
    DOI:  https://doi.org/10.1038/s41467-025-65081-8
  27. Hereditas. 2025 Nov 20. 162(1): 230
    Mapping the global research landscape of mitophagy in Parkinson's disease: a bibliometric and visualization analysis.
    Junqiao Zhao, Qian Wang, Yan Cao, Huimin Shan, Shifen Xu.
      Parkinson's disease (PD) is closely linked to mitochondrial dysfunction and mitophagy, a key mechanism in PD pathogenesis. However, no dedicated bibliometric analysis of mitophagy in PD exists. This study used data from the Web of Science Core Collection to map the global research landscape of mitophagy in PD. The analysis of 1,578 publications (2007-2024) identifies the United States as the most productive country. McGill University ranks as the top institution, and Nobutaka Hattori is the most prolific author. The journal Autophagy is the journal with the highest number of publications in this field. Core research themes included PINK1/Parkin, mitochondrial quality control, α-synuclein, neuroinflammation, and ferroptosis. The study provides insights into the current status of global collaboration and translational progress in this field. Future efforts should aim to further explore new pathways, enhance clinical translation, and promote collaborative partnerships to advance research and address challenges in the field.
    Keywords:  Bibliometric analysis; Mitophagy; PINK1/Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s41065-025-00544-y
  28. Exp Mol Med. 2025 Nov 18.
    Failure of lysosomal acidification and endomembrane network in neurodegeneration.
    Seo-Hyun Kim, Young-Sin Cho, Yong-Keun Jung.
      Lysosomes have emerged as central hubs in the regulation of the endomembrane system, extending beyond degradation to coordinate organelle communication. Central to this regulatory role is vacuolar-type H+-ATPase (V-ATPase), a proton pump that acidifies the lysosomal lumen to enable hydrolase activity and support proteostasis. In addition to its lysosomal functions, V-ATPase influences the physiology of other organelles, including the endoplasmic reticulum (ER), Golgi apparatus and mitochondria, through both direct and indirect mechanisms involving acidification-dependent processes, such as protein folding, vesicular trafficking and stress responses. V-ATPase dysfunction compromises interorganelle communication through multiple mechanisms, including impaired calcium and lipid exchange at contact sites, disrupted organelle positioning and defective autophagic and stress signaling. In neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, V-ATPase impairment contributes to lysosomal storage pathology, ER stress, Golgi fragmentation and mitochondrial dysfunction. ER-endolysosome tethering proteins and mitochondria-lysosome contacts are particularly sensitive to pH and trafficking defects. These disruptions result in a cascade of organelle dysfunction and contribute to disease progression. Here, in this Review, we highlight how V-ATPase governs both local lysosomal function and broader organelle network integrity, positioning it as a critical regulator of endomembrane homeostasis and a potential therapeutic target in neurodegenerative conditions.
    DOI:  https://doi.org/10.1038/s12276-025-01579-x
  29. Autophagy. 2025 Nov 20.
    Regulation of pexophagy by a novel TBK1-MARCHF7-PXMP4-NBR1 Axis in PEX1-depleted HeLa cells.
    Yong Hwan Kim, Joon Bum Kim, Ji-Eun Bae, Na Yeon Park, Seong Hyun Kim, Jae-Young Um, Dong-Seok Lee, Kyu Sun Lee, Peter K Kim, Doo Sin Jo, Dong-Hyung Cho.
      Peroxisomes are essential for lipid metabolism and redox balance, with pexophagy playing a critical role in maintaining cellular homeostasis. However, the regulatory mechanisms of pexophagy remain unclear. Through functional screening, we identified MARCHF7 as a novel E3 ligase regulating pexophagy. MARCHF7 depletion impaired pexophagic flux under PEX1 knockdown conditions. MARCHF7 binds to PXMP4 and promotes its ubiquitination at lysine 20 in PEX1-deficient cells. Depletion of PXMP4 impairs pexophagy, and reconstitution with the PXMP4 lysine 20 ubiquitination-defective mutant failed to rescue pexophagy. PEX1 depletion also induces TBK1 phosphorylation at serine 172, activating TBK1, which subsequently phosphorylates MARCHF7. This activation is driven by ROS accumulation, which reduces PXMP4 ubiquitination and prevents peroxisome loss. Furthermore, downregulation of MARCHF7 or PXMP4 impairs NBR1 recruitment to peroxisomes, suggesting that ubiquitinated PXMP4 acts as a recognition signal for NBR1. Collectively, our findings establish the TBK1-MARCHF7-PXMP4-NBR1 axis as a key regulatory pathway for pexophagy in response to PEX1 depletion.
    Keywords:  MARCHF7; PEX1; PXMP4; TBK1; peroxisome; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593585
  30. bioRxiv. 2025 Oct 02. pii: 2025.10.02.680077. [Epub ahead of print]
    Sequelae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
    Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.
      How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals >65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by chemically promoting autophagosome generation, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in in mitochondria-intrinsic mechanisms to avoid loss of energy production.
    DOI:  https://doi.org/10.1101/2025.10.02.680077
  31. Cell Death Discov. 2025 Nov 17. 11(1): 533
    DEPTOR regulates nucleus pulposus cell senescence through the mTORC1/S6K1/ATG1 pathway to alleviate intervertebral disk degeneration.
    Hui Lu, Zhiming Liu, Yan Wang, Shuo Han, Xianjuan Zhang, Rong Liu, Yusi Gao, Hualei Liu, Hao Tao, Xuexiao Ma, Zhu Guo.
      This study aimed to determine the molecular mechanisms by which the DEP domain-containing mTOR-interacting protein (DEPTOR) regulates the senescence of nucleus pulposus (NP) cells (NPCs), alleviating intervertebral disk degeneration (IDD). This study investigated how DEPTOR regulates the mechanistic target of rapamycin complex 1 (mTORC1)/S6 kinase beta-1 (S6K1)/autophagy-related gene 1 (ATG1) pathway to regulate senescence-associated secretory phenotype (SASP) and cellular autophagy in NPCs. Isobaric tags for relative and absolute quantitation was used to measure the differences in protein expression between degenerated and normal intervertebral disk tissues. Western blotting and immunofluorescence were used to quantify DEPTOR levels in NP tissues. DEPTOR was overexpressed in vitro, and changes in autophagy and SASP were monitored to determine its effects on NPCs. Moreover, lentiviral overexpression of S6K1 (LV-S6K1) and siRNA-mediated knockdown of ATG1 (ATG1-ShRNA) in both in vitro and in vivo models were used to verify whether DEPTOR stimulates autophagy in NPCs via ATG1 and inhibits SASP through S6K1. The results demonstrated that degenerated intervertebral disks had lower DEPTOR levels. Matrix metalloproteinases, inflammatory cytokines, chemokines, and aging-related proteins were downregulated when DEPTOR was overexpressed in NPCs. Furthermore, autophagic activity was stimulated, SASP secretion was inhibited, and extracellular matrix synthesis was increased. ATG1 knockdown decreased the capacity of DEPTOR to promote cellular autophagy and inhibit SASP, whereas S6K1 overexpression diminished DEPTOR-mediated SASP inhibition. DEPTOR attenuates IDD by inhibiting SASP secretion via the mTORC1/S6K1 pathway and promoting autophagy in NPCs via the mTORC1/ATG1 pathway.
    DOI:  https://doi.org/10.1038/s41420-025-02819-9
  32. Turk Arch Pediatr. 2025 11 03. 60(6): 577-589
    Cell Trafficking Disorders Play an Important Role in the Pathogenesis of Skeletal Dysplasias.
    Beyhan Tüysüz.
      Cell trafficking is the transfer of signals and metabolic products between cell compartments to maintain crucial biological functions. In recent years, more than 370 genes have been shown to be associated with defects in cellular transport. The aim of this review is to draw attention to the importance of cell trafficking in the pathogenesis of skeletal dysplasia and to attempt to establish a relationship between clinical findings and the functions of the disrupted proteins. Cell trafficking disorders are divided into four main categories: defects in proteins involved in the transport of molecules (cargo) from the cell to the outside (exocytic pathway) or from the outside to the inside (endocytic pathway) and related to the cytoskeleton, membrane contact sites, and autophagy. A number of skeletal dysplasias result from deficiencies in proteins across different categories of cell trafficking, including glycosylation and lysosomal disorders, which are skeletal involvement. It is noteworthy that genes affected in skeletal dysplasias related to cell trafficking are impaired in signaling pathways involved in the embryonic development of bone, membranous and endochondral ossification, and skeletal morphogenesis. Studies investigating the role of cell trafficking in the development of skeletal dysplasias will shed light on the disease's pathogenesis and increase the potential for developing new therapeutic agents.
    Keywords:  Autophagy; cell trafficking disorders; cytoskeleton; membrane contact sites; motorproteins; organelles; vesicular trafficking
    DOI:  https://doi.org/10.5152/TurkArchPediatr.2025.25159
  33. Cell Death Dis. 2025 Nov 20.
    Functional analyses and integrated mechanisms of cellular destruction by L-amino acid oxidase.
    Krisna Prak, Christin Luft, Eliona Tsefou, Carlos Chávez-Olórtegui, Janos Kriston-Vizi, Robin Ketteler, Vania M M Braga.
      Snakebite accidents are prevalent worldwide and cause a spectrum of severe clinical manifestations and result in a reduction of patient quality of life and economic income. A major bottleneck in envenomation treatment is our limited understanding of how venom toxins perturb specific cellular processes involved in tissue necrosis. Here, we address this knowledge gap and define the cellular mechanisms via which cell death is triggered by the snake toxin L-amino acid oxidase (LAAO). LAAO is a highly toxic enzyme present in various venoms that causes tissue necrosis, edema, coagulopathies, and organ failure. Here, we identify the residues essential for LAAO oxidation and obtain a catalytically inactive LAAO mutant, which is unable to reproduce the cellular phenotypes. Striking cellular defects are triggered by a catalysis-dependent increase in oxidative stress, via H2O2 (reaction byproduct). LAAO uptake by cells leads to a decrease in lysosome number and size and inhibits autophagy flux. In parallel, mitochondria function is impaired by severe proton leakage, and mitochondrial fission is stimulated, causing their engulfment by autophagosomes. However, mitochondrial clearance is prevented by the lysosomal defects. The concurrent shutdown of cell respiration and energy consumption indicates that LAAO catalysis reduces both metabolism and cell fitness. Thus, essential organelles are coordinately impaired by LAAO activity, accelerating cell demise. Considering the multi-organelle impairment, strategies to reduce organelle injury after LAAO exposure may be effective to maintain critical cell functions and strengthen adaptive responses against cytotoxicity.
    DOI:  https://doi.org/10.1038/s41419-025-08187-7
  34. Blood Adv. 2025 Nov 19. pii: bloodadvances.2025017486. [Epub ahead of print]
    Role of Rubicon in Platelets: A Promoter of Thrombosis but Not an Autophagy Repressor.
    Hammodah R Alfar, Elizabeth R Driehaus, Alexis N Smith, Daniëlle Marije Coenen, Dlovan F D Mahmood, Jeremy P Wood, Sidney W Whiteheart.
      Rubicon (RUN domain Beclin-1-interacting and cysteine-rich-containing protein) is a negative regulator of autophagy in nucleated cells; however, its role in platelets is unstudied. Here, we identify an autophagy-independent role for Rubicon in arterial thrombosis. Mice with a platelet/megakaryocyte-specific deletion of Rubicon (RUBCN-/-) showed normal circulating platelet counts, with a slight increase in platelet size. The basal levels of autophagy-related, vesicle-elongation proteins (i.e., ATG5, ATG7, Syntaxin 17, LC3, and Rab7) were unaffected, and there was no disruption in canonical platelet signaling pathways upon activation. Platelet secretion from all three granule classes remained intact. Aggregation in response to thrombin, convulxin, or botrocetin was unaffected. There was no overt defect in activation-dependent autophagic flux (i.e., loss of LC3 or p62). However, RUBCN-/- mice had a significant thrombosis defect in the FeCl3-induced, carotid artery injury model, but no defect in the tail transection hemostasis model. An intrinsic platelet defect was confirmed using microfluidics, where RUBCN-/- platelets had reduced collagen binding under flow at high shear flow but not low shear. RUBCN-/- platelets also had impaired surface exposure of phosphatidylserine (PS) following thrombin and convulxin activation, though there was no effect on total anoctamin 6 (ANO6), which contributes to PS exposure. There was no effect on platelet endocytosis and only modest reductions in mitochondrial membrane potential with a slight delay in clot contraction, suggesting that Rubicon contributes to late stages of platelet function. Collectively, our findings demonstrate that Rubicon contributes to thrombosis and procoagulant platelet formation in a manner that appears independent of classical autophagy.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017486
  35. bioRxiv. 2025 Oct 02. pii: 2025.10.01.679551. [Epub ahead of print]
    Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.
    Jacob K Hilton, Yifei Lin, Eric Sefah, Justin C Deme, Joanne L Parker, Matthew J Langton, Michael Grabe, Susan Lea, Simon Newstead, Joseph A Mindell.
      Lysosomes process cellular waste and coordinate responses to metabolic challenge. Central to lysosomal homeostasis are phosphoinositide lipids, key signaling molecules which establish organelle identity, regulate membrane dynamics and are tightly linked to the pathophysiology and therapy of lysosomal storage disorders, neurodegeneration, and cancer. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) interacts with multiple lysosomal membrane proteins and plays a critical role in regulating lysosomal pH by directly inhibiting the chloride/proton antiporter ClC-7, though the molecular mechanism of this inhibition remains unclear. Here, using a combination of functional, structural, and computational analysis, we demonstrate that PI(3,5)P2 binding dramatically remodels the structure of ClC-7 by inducing close association between cytosolic and transmembrane domains. Disease-causing mutations show increased transport activity through loss of PI(3,5)P2 binding and subsequent inhibition. Conversely, ClC-7 activation is correlated with dissociation and increased disorder of the cytoplasmic domain along with novel transmembrane domain conformations, revealing a mechanistic link between specific lysosomal lipids, transporter regulation, and the enigmatic basis of the ClC-7 slow gate.
    DOI:  https://doi.org/10.1101/2025.10.01.679551
  36. bioRxiv. 2025 Oct 04. pii: 2025.10.03.680346. [Epub ahead of print]
    The Lysosome Surface is an Unappreciated Hub for Vasopressin V2 Receptor Signaling.
    Emmanuel Flores-Espinoza, Hyunggu Hahn, Alex R B Thomsen.
      G protein-coupled receptors (GPCRs) have traditionally been understood to signal through heterotrimeric G proteins exclusively from the cell surface followed by β-arrestin (βarr)-mediated desensitization and receptor internalization into endosomes. However, this view has evolved significantly with growing evidence showing that some GPCRs continue to signal from endosomes after their internalization as well as from other intracellular organelles. The vasopressin V2 receptor (V2R) exemplifies this paradigm shift as it promotes robust endosomal G protein before being sorted to lysosomes for degradation. Intriguingly, recent observations suggest that the lysosomal surface itself holds a substantial pool of heterotrimeric G proteins, raising the possibility that GPCRs such as the V2R may stimulate signaling from this subcellular region. To investigate this, we here employed a NanoBiT bystander approach to track intracellular V2R trafficking and transducer activation in real-time. Our results show that activated V2R is trafficked relatively fast to lysosomes where it retains the ability to couple to both G proteins and βarrs. Applying nanobody/intrabody biosensors, we further demonstrated that the V2R activates endogenous G proteins and βarrs at the lysosomal surface and that inhibition of V2R translocation to endolysosomal compartments blunts its ability to stimulate G protein signaling. Together, these findings suggest that the lysosomal surface serves as an unappreciated hub for signaling by some GPCRs before they eventually are engulfed into the lysosomal lumen for degradation.
    One-sentence summary: Upon activation, the vasopressin V2 receptor is internalized and sorted to the lysosomal membrane, where it activates G proteins and β-arrestins.
    DOI:  https://doi.org/10.1101/2025.10.03.680346
  37. Nat Commun. 2025 Nov 19. 16(1): 10181
    PRDX1 promotes testosterone synthesis and attenuates aging via redox regulation of ATG4B to modulate lipophagy.
    Hanbin Zhang, Ke Ma, Yuge Zhuang, Xixian Cen, Xiaoyuan Zhang, Shipeng Ruan, Hongrui Feng, Runduan Yi, Zicong Huang, Chuyu Huang, Minyu Xie, Lan Tang, Xiong Cao, Guofei Zhang, Xiangjin Kang, Yong Fan, Zhenguo Chen.
      Testosterone insufficiency disrupts spermatogenesis and expedites male aging. Autophagy facilitates testosterone synthesis. However, a molecular reduction mechanism of autophagy-related protein 4 homolog B (ATG4B) has not been established. Herein, we reveal that peroxiredoxin 1 (PRDX1) is clinically associated with male fertility disorders. Adult mutant mice with Leydig cell (LC)-specific deletion of the Prdx1 gene exhibit premature testicular aging and infertility. A series of in vivo and in vitro experiments, in combination with multi-omics analyses, demonstrate that PRDX1 inactivation impairs lipophagy and testosterone synthesis in LCs. Mechanistically, Cys52 and Cys173 in PRDX1 specifically target the redox-site Cys78 in ATG4B to preserve the delipidating activity of Cys74 in ATG4B, thereby promoting autophagic flux. Furthermore, PRDX1 dysfunction exacerbates testicular and systematic aging in aged mice, which can be alleviated by a 2-cysteine mimic, ebselen. Collectively, our findings demonstrate that PRDX1 promotes lipophagy and testosterone synthesis by regulating ATG4B. Our findings also propose the potential application of ebselen in the prevention and treatment of aging-related disorders, including late-onset hypogonadism.
    DOI:  https://doi.org/10.1038/s41467-025-65328-4
  38. Sci Rep. 2025 Nov 19. 15(1): 40805
    Treatment with L-type amino acid transporter 1 inhibitor JPH203 enhances protein synthesis in C2C12 myotubes.
    Junya Takegaki, Takaoki Saneyasu, Kazuhisa Honda.
      Excessive muscle protein synthesis causes skeletal muscle hypertrophy. Essential amino acids are substrates for muscle proteins and stimulate muscle protein synthesis. Several essential amino acids are taken up into muscle cells through L-type amino acid transporter 1 (LAT1). However, LAT1 may influence protein synthesis in an amino acid uptake-independent manner. Here, we investigated the effects of LAT1 inhibition on protein synthesis in C2C12 myotubes and the associated mechanisms. JPH203 (50 μM), a selective inhibitor of LAT1, stimulated protein synthesis without changing expression of phosphorylated p70S6K (T389) and 4EBP1 (T37/46), an indicator of mTORC1 activity. Culturing in amino acid-free media did not suppress JPH203-induced protein synthesis. The mTORC1 inhibitor rapamycin (100 nM) did not suppress JPH203-induced protein synthesis. ATP-competitive mTOR inhibitor AZD8055 (1 μM) suppressed JPH203-induced protein synthesis. JPH203 treatment increased intracellular glutamine concentration. These results suggest that inhibition of LAT1 function augments muscle protein synthesis, possibly through the activation of rapamycin-insensitive mTOR signaling; elevated intracellular glutamine levels may contribute to the enhancement of muscle protein synthesis induced by LAT1 inhibition.
    Keywords:  L-type amino acid transporter 1; Leucine; Mechanistic target of rapamycin; Muscle protein synthesis; Myotubes
    DOI:  https://doi.org/10.1038/s41598-025-24534-2
  39. Nat Commun. 2025 Nov 21. 16(1): 10239
    Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration.
    Xun Sun, Debasis Saha, Xue Wang, Cecilia Mörman, Rebecca Sternke-Hoffmann, Juan Atilio Gerez, Fátima Herranz-Trillo, Roland Riek, Wenwei Zheng, Jinghui Luo.
      Spermine, a pivotal player in biomolecular condensation and diverse cellular processes, has emerged as a focus of investigation in aging, neurodegeneration, and other diseases. Despite its significance, the mechanistic details of spermine remain incompletely understood. Here, we describe the distinct modulation by spermine on Alzheimer's Tau and Parkinson's α-synuclein, elucidating their condensation behaviors in vitro and in vivo. Using biophysical techniques including time-resolved SAXS and NMR, we trace electrostatically driven transitions from atomic-scale conformational changes to mesoscopic structures. Notably, spermine extends lifespan, ameliorates movement deficits, and restores mitochondrial function in C. elegans models expressing Tau and α-synuclein. Acting as a molecular glue, spermine orchestrates in vivo condensation of α-synuclein, influences condensate mobility, and promotes degradation via autophagy, specifically through autophagosome expansion. This study unveils the interplay between spermine, protein condensation, and functional outcomes, advancing our understanding of neurodegenerative diseases and paving the way for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-025-65426-3
  40. Nat Neurosci. 2025 Nov 21.
    Astrocytic Sox9 overexpression in Alzheimer's disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function.
    Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen.
      Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9-MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s41593-025-02115-w
  41. Nat Struct Mol Biol. 2025 Nov 17.
    ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth.
    Helin Elhan, Alicia Damm, Justin L Korfhage, Daniel Álvarez, Mehdi Zouiouich, Francesca Giordano, Stefano Vanni, Thomas J Melia, Abdou Rachid Thiam.
      Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expansion is reduced when DGAT2 is inhibited. This synergistic action with DGAT2 prevents the buildup of nonmembrane lipids within the endoplasmic reticulum and favors TAG synthesis on the LD surface.
    DOI:  https://doi.org/10.1038/s41594-025-01689-0
  42. Commun Biol. 2025 Nov 19. 8(1): 1606
    TORC2 inactivation promotes heterochromatin formation in rDNA and prolongs viability of quiescent fission yeast cells.
    Hayato Hirai, Kunihiro Ohta.
      A large amount of the energy produced by glucose is consumed in the biogenesis of ribosomes, the cellular machinery for protein synthesis. Recent studies suggest that a low-calorie diet and the suppression of ribosome biogenesis can extend lifespan. However, the molecular mechanisms underlying these phenomena remain elusive. Here, we demonstrate that TORC2 (TOR complex 2) promotes ribosomal RNA (rRNA) transcription by facilitating the association of Paf1C (RNA polymerase II-associated factor 1 complex) with the rDNA region. Under glucose starvation, inactivation of the TORC2-Gad8 pathway leads to the dissociation of Paf1C from rDNA, thereby promoting heterochromatin formation and transcriptional repression. This mechanism is distinct from TORC1-mediated gene regulation of rDNA. Additionally, simultaneous inactivation of the redundant TORC1 and TORC2 pathways in nutrient-rich conditions leads to robust rDNA heterochromatin formation and rRNA transcriptional suppression, which is associated with prolonged viability of quiescent cells. This extension of viability is attenuated by the disruption of the H3K9 methyltransferase Clr4. These results suggest that robust heterochromatin formation in the rDNA region may support sustained survival of quiescent cells.
    DOI:  https://doi.org/10.1038/s42003-025-08953-5
  43. J Biol Chem. 2025 Nov 17. pii: S0021-9258(25)02805-4. [Epub ahead of print] 110953
    Differential ion selectivity and disease-associated dysfunction of TRPML channels revealed by patient and engineered mutants.
    Braden E Rue, Anna M Dischler, Lyndsie A Salvagio, Michael Zhu, Gabriel Xu, Patrick C Flores, Chelsea L Donovan, Xin Liu, Taylor F Minckley, Brooke Agulnek, Yan Qin.
      The endolysosomal TRPML (transient receptor potential mucolipin) channels play key roles in regulating lysosomal trafficking, signaling, and function. While mutations in TRPML1 cause mucolipidosis type IV (MLIV), the functional consequences of many disease-associated mutations remain unclear. In this study, we used live-cell confocal imaging in HeLa cells to comprehensively characterize the subcellular localization and cation (Ca2+ and Zn2+) permeability of TRPML1-3, ten TRPML1 MLIV patient-derived mutants, and engineered pore mutants. We showed that TRPML1 and TRPML3 permeate both Ca2+ and Zn2+, whereas TRPML2 conducts only Ca2+. Subcellular localization analyses revealed that TRPML1 and TRPML2 localize predominantly to lysosomes, while TRPML3 is preferentially localized to the ER. Among the ten patient-derived TRPML1 mutants, nine exhibited severely impaired agonist-mediated Ca2+ and Zn2+ permeability, indicating severe functional loss. In contrast, the F408Δ mutant, associated with a milder phenotype, retained partial ion permeability and was the only mutant capable of constitutive Ca2+ permeation without agonist stimulation. Interestingly, we found that non-functional, lysosome-localized TRPML1 mutants are associated with more severe disease phenotypes than those retained in the ER, suggesting that lysosomal localization of non-functional TRPML1 may have dominant-negative or toxic effects. Finally, through structure-guided mutagenesis, we generated a metal-selective TRPML1 mutant, I468V, that is permeable to Ca2+ but not to Zn2+, providing a new tool for dissecting the distinct physiological roles of Zn2+ and Ca2+ in TRPML1-mediated processes. Together, these findings provide new insights into how TRPML1 mutations disrupt subcellular localization, ion permeability, and selectivity, which contribute to the variable clinical spectrum of MLIV.
    Keywords:  calcium; lysosome; mucolipidosis type IV; permeability; transient receptor potential channels (TRP channels); zinc
    DOI:  https://doi.org/10.1016/j.jbc.2025.110953
  44. Eur J Pharmacol. 2025 Nov 14. pii: S0014-2999(25)01130-6. [Epub ahead of print]1008 178376
    Trimetazidine alleviates heart failure after myocardial infarction by promoting PINK1/parkin-mediated mitophagy and suppressing GPX4-dependent ferroptosis.
    Zian Wang, Xuan Liu, Yunjie Wu, Guangjian Chen, Jia Wang, Yuewen Qi, Ruowen Wu, Jiancheng Wang, Qinghai Meng, Yu Li.
      Heart failure (HF) remains a prevalent complication following myocardial infarction (MI), characterized by mitochondrial dysfunction and cardiomyocyte ferroptosis, which jointly contribute to myocardial remodeling and impaired cardiac function. The present study aims to evaluate the cardioprotective efficacy and underlying mechanisms of trimetazidine (TMZ), a clinically established anti-anginal agent, in alleviating post-MI HF regulation of mitochondrial quality control and ferroptosis inhibition. Utilizing an in vivo mouse model established by left coronary artery ligation, TMZ administration significantly improved cardiac function, delayed ventricular remodeling, and reduced myocardial infarct size. Concurrently, TMZ treatment significantly reduced myocardial oxidative stress, evidenced by elevated antioxidant enzyme levels (GSH and SOD), decreased malondialdehyde (MDA), and lower intracellular Fe2+ accumulation, along with upregulation of key anti-ferroptotic markers GPX4 and SLC7A11. Complementary in vitro experiments on oxygen-glucose deprivation (OGD)-injured HL-1 cardiomyocytes confirmed that TMZ preserved cellular viability in a dose-dependent manner by inhibiting ferroptosis. Furthermore, TMZ effectively restored mitochondrial membrane potential, improved mitochondrial morphology, promoted mitophagy by increasing PINK1/Parkin pathway activation, and corrected mitochondrial dynamics through upregulation of MFN1 and downregulation of DRP1. Notably, when the mitophagy inhibitor Mdivi-1 or PINK1 siRNA was used, the protective effect of TMZ was reversed by inhibition of mitophagy. This suggests that mitophagy activated through PINK1/Parkin signaling is essential for TMZ-mediated myocardial protection and ferroptosis suppression. Molecular docking further validated TMZ's potential direct interaction with PINK1. In conclusion, these findings demonstrate that TMZ ameliorates post-MI heart failure by orchestrating mitochondrial quality control through promotion of mitophagy and suppression of GPX4-dependent ferroptosis, offering novel mechanistic insight into its therapeutic potential in the management of ischemic heart disease.
    Keywords:  Ferroptosis; GPX4; Heart failure; Mitophagy; Myocardial infarction; PINK1/Parkin; Trimetazidine
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178376
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