bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–12–21
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. AUTOPHAGIC punctum a self-sensing vacuole/lysosome: V-ATPase dysfunction activates selective autophagy.
  2. TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration.
  3. Complex role of mTOR signaling pathway in glioblastoma and its stem cells.
  4. Maspardin/SPG21 controls lysosome motility and TFEB phosphorylation through RAB7 positioning.
  5. STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis.
  6. Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
  7. Catabolic degradation of endothelial VEGFA via autophagy.
  8. Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity.
  9. Proteomic analysis links truncated tau to lysosome motility, autophagy, and endo-lysosomal dysfunction.
  10. NoxO1 promotes endosome formation and reduces intracellular vesicle processing.
  11. FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
  12. Spermidine deficiency induces BNIP3/LC3B-mediated mitophagy in the salivary glands of accelerated aging mice.
  13. Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.
  14. FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth.
  15. Distinct Roles of Urolithin A and Spermidine in Mitophagy and Autophagy: Implications for Dietary Supplementation.
  16. Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
  17. RLX-201, a Novel mTORC1 Inhibitor With Potential to Promote Skin Longevity and Cellular Health.
  18. cAMP promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.
  19. Physcomitrium patens: an emerging model for autophagy study.
  20. GPNMB, LRRK2, and lysosome exocytosis in Parkinson's.
  21. Pathogenic Role of mTOR Signaling in Cardiometabolic Disease: Implications for Heart, Liver, and Kidney Dysfunction.
  22. Autophagy-related genes and encoded proteins' prognostic significance in various cancer types: A molecular perspective.
  23. Protein quality control: from molecular mechanisms to aging and disease - EMBO workshop, May 18-23, 2025, Hersonissos, Greece.
  24. Unveiling the neuroprotective power: the role of autophagy in remote ischemic conditioning.
  25. Age-related nigral downregulation of the Parkinson's risk factor FAM49B primes human microglia for inflammaging.
  26. Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
  27. Endothelial Transcription Factor EB Protects Against Doxorubicin-Induced Endothelial Toxicity and Cardiac Dysfunction.
  28. Human umbilical cord-derived mesenchymal stem cells ameliorate non-alcoholic fatty liver disease via activating TFEB-mediated autophagy in male mice.
  29. Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation-Resistant SPAST Mutation.
  30. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  31. Targeting autophagy kinases: from mechanisms to therapy with novel small molecules.
  32. CRISPR/Cpf1-mediated editing of PINK1 in induced pluripotent stem cells.
  33. Multilayered regulation of longevity in Caenorhabditis elegans.
  34. Less Inflammatory Debris, Improved Immunity from Immune Detox: A New Perspective on the Benefits of Exercise in Chronic Disease.
  35. A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.
  36. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  37. Autophagy is required for the development and functionality of lacrimal gland-like organoids.
  38. Autophagosome degraders: a novel therapeutic strategy with broad application potential in human diseases.
  39. Inhibition of STING-mediated antiviral innate immunity activation by CD97 via modulation of ER-phagy.
  40. Lysosome Evanescence Mediates Autophagic Flux Impairment in Glucose Imbalanced Environments.
  41. Enhanced Lysosomal Activity Prevents Infection with PrPSc and the Seeding Activity of α-Synuclein & Tau Prions.
  42. Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases.
  43. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  1. Autophagy. 2025 Dec 18.
    AUTOPHAGIC punctum a self-sensing vacuole/lysosome: V-ATPase dysfunction activates selective autophagy.
    Yuxiang Huang, Daniel J Klionsky.
      Macroautophagy/autophagy has long been viewed as being strictly dependent on vacuolar or lysosomal acidity, with the vacuolar-type H+ -translocating ATPase (V-ATPase) functioning mainly as a proton pump that sustains degradation. Our recent paper overturns this paradigm, revealing that loss of V-ATPase activity paradoxically induces a selective autophagy program in nutrient-replete Saccharomyces cerevisiae. Vacuolar deacidification triggers a signaling cascade through the Gcn2-Gcn4/ATF4 integrated stress response, which drives Atg11-dependent ribophagy even when TORC1 remains active. This "V-ATPase-dependent autophagy" operates as a self-corrective feedback loop: when the vacuole's degradative capacity falters, it signals its own dysfunction to restore homeostasis. Tryptophan and NAD+ metabolism modulate this response, linking metabolic balance to autophagy induction. This discovery reframes the vacuole/lysosome from a passive endpoint to an active sensor of cellular integrity. It also challenges the use of V-ATPase inhibitors such as bafilomycin A1 as neutral autophagy flux blockers, because inhibition itself can stimulate autophagy induction. Collectively, these findings position the V-ATPase as a bidirectional regulator - both gatekeeper and sentinel - governing how cells translate organelle stress into adaptive autophagy.
    Keywords:  ATF4/Gcn4; NAD+ metabolism; V-ATPase; ribosome biogenesis; selective autophagy; tryptophan metabolism
    DOI:  https://doi.org/10.1080/15548627.2025.2604345
  2. Adv Sci (Weinh). 2025 Dec 17. e09927
    TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration.
    Maria G Herrera, Lena Kühn, Lisa Jungbluth, Verian Bader, Laura J Krause, David Kartte, Elias Adriaenssens, Sascha Martens, Jörg Tatzelt, Carsten Sachse, Konstanze F Winklhofer.
      Optineurin is an autophagy receptor that plays an important role in the selective degradation of mitochondria, protein aggregates, and intracellular pathogens. It recognizes ubiquitylated cargo by its ubiquitin-binding in ABIN and NEMO (UBAN) domain and recruits the autophagic machinery through its LC3-interacting region (LIR) domain. Phosphorylation of Optineurin by TANK-binding kinase 1 (TBK1) increases the binding of Optineurin to both ubiquitin chains and lipidated microtubule-associated protein light chain 3 (LC3). Optineurin has been reported to form foci at ubiquitylated cargo, but the underlying mechanism and how these foci are linked to selective autophagy has remained largely unknown. This study shows that phosphorylation of Optineurin by TBK1 induces the formation of filaments that phase separate upon binding to linear polyubiquitin. LC3 anchored to unilamellar vesicles co-partitions into Optineurin/polyubiquitin condensates, resulting in the local deformation of the vesicle membrane. Thus, the condensation of filamentous Optineurin with ubiquitylated cargo promotes the nucleation of cargo and its subsequent alignment with LC3-positive nascent autophagosomes, suggesting that co-condensation processes ensure directionality in selective autophagy.
    Keywords:  Optineurin; TBK1; autophagy; phase separation; ubiquitin
    DOI:  https://doi.org/10.1002/advs.202509927
  3. Adv Biol Regul. 2025 Dec 11. pii: S2212-4926(25)00070-3. [Epub ahead of print]100 101143
    Complex role of mTOR signaling pathway in glioblastoma and its stem cells.
    Austin B Carpenter, Ariel Sacknovitz, Simon Hanft, Chirag D Gandhi, Meena Jhanwar-Uniyal.
      Mechanistic target of rapamycin (mTOR: aka mammalian target of rapamycin), a serine threonine kinase, functions by forming two multiprotein complexes designated mTORC1 and mTORC2. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Aberrant signaling of mTOR is shown to be associated with tumorigenesis of numerous malignancies including glioblastoma (GBM). mTORC1 and mTORC2 activate downstream substrates that execute cellular and metabolic functions. Experimental models have provided evidence of the existence of cancer stem cells (CSCs), also known as tumor-initiating cells within the tumor mass, that may play an active role in development, progression and reformation of GBM. In addition, presence of highly infiltrative CSCs in the peritumoral region of GBM may appear to play an important role in recurrence of disease. Since rapamycin and its analogues are less effective in treatment of GBM, the use of ATP-competitive dual inhibitors of mTORC1 and mTORC2 have been increasingly investigated. These attempt to suppress GBM growth by pharmacodynamically inhibiting phosphorylation of the mTORC1 substrates S6K Ser235/236 and 4E-BP1 Thr37/46. These inhibitors also cause down-regulation of mTORC2 substrate AKT Ser473. These reactions result in reduction of cell growth and migration. Notably, these inhibitors of mTOR also alter self-renewal and growth of CSC of GBM. The aim of this review is to reiterate the use of mTOR inhibitors in the treatment of GBM and its stem cells associated with progression and recurrence of the disease. In addition, understanding the peritumor area of GBM is a crucial means to control the recurrence of the disease.
    Keywords:  Glioblastoma; Stem cells; mTOR; mTORC1; mTORC2 cancer
    DOI:  https://doi.org/10.1016/j.jbior.2025.101143
  4. J Cell Biol. 2026 Feb 02. pii: e202501135. [Epub ahead of print]225(2):
    Maspardin/SPG21 controls lysosome motility and TFEB phosphorylation through RAB7 positioning.
    Thomas Jacqmin, Florentine Gilis, Martine Albert, Jean-François Gaussin, Michel Jadot, Marielle Boonen.
      Spastic paraplegia 21 is a neurodegenerative disease characterized by the degeneration of corticospinal axons. It is caused by mutations in the SPG21 gene, which encodes maspardin, a cytosolic protein of unknown function that associates with the late endosomal/lysosomal membrane. Intriguingly, we found that the phosphorylation level of the transcription factor EB (TFEB), a master regulator of the CLEAR gene network, is decreased in SPG21 knockout cells, leading to TFEB nuclear translocation. Our investigations revealed that the Rag-mediated presentation of TFEB to the mTOR kinase and its subsequent phosphorylation is disturbed by a delocalization of the RAB7 GTPase, a maspardin-binding partner, from retromer-positive late endosomes to lysosomes. This redistribution decreases the interaction between RAB7 and its GTPase-activating protein (GAP), TBC1D5. Consequently, RAB7 remains primarily GTP-bound, recruiting more FYCO1 to lysosomes and promoting the anterograde movement of these organelles along microtubules. These findings identify maspardin as a newly discovered RAB7 effector and shed light on several consequences of its deficiency.
    DOI:  https://doi.org/10.1083/jcb.202501135
  5. Cell Signal. 2025 Dec 12. pii: S0898-6568(25)00737-5. [Epub ahead of print]139 112322
    STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis.
    Yuyuan Wang, Yu Luo, Fei Zhou, Dan Li.
      Recently several studies have identified that transcription factor EB (TFEB) and transcription factor E3 (TFE3) are the crucial regulators bridging the crosstalk between lysosomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Moreover, this TFEB/TFE3-mediated pathway establishes an essential negative feedback loop, revealing a novel self-regulatory mechanism in innate immunity, which suppresses IRF3 phosphorylation and IFN secretion, reduces caspase-3 activation, and enhances cell survival. Collectively, these findings unveil a critical role for TFEB/TFE3 in the maintenance of immune homeostasis, highlighting their functions in preventing excessive immune responses and protecting cell survival. In this review, we will summarize these findings and discuss the new insights they bring to our understanding of the interplay among the cGAS-STING pathway, lysosomal function, and innate immunity.
    Keywords:  Autophagy; Lysosomes; TFE3; TFEB; cGAS-STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112322
  6. Aging Dis. 2025 Dec 14.
    Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
    Sen Huang, Ang Li, Yixia Ling, Xinyu Yang, Jiayu Wang, Jing Yuan, Dajiang Qin, Xiaoli Yao.
      Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1G93A, TDP43A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.
    DOI:  https://doi.org/10.14336/AD.2025.1224
  7. J Biol Chem. 2025 Dec 18. pii: S0021-9258(25)02808-X. [Epub ahead of print]302(1): 110956
    Catabolic degradation of endothelial VEGFA via autophagy.
    Thomas Neill, Carolyn G Chen, Simone Buraschi, Renato V Iozzo.
      
    DOI:  https://doi.org/10.1016/j.jbc.2025.110956
  8. Nat Commun. 2025 Dec 13.
    Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity.
    Yonghua Li, Min Sheng, Weijie Li, Simin Liu, Botao Wang, Bing Liu, Mei Luo, Xiao Zhou, Qiaoxi Xia, Shihong Hong, Ziyuan Zheng, Shi-Yuan Cheng, Xiaobing Jiang, Junjun Li, Tianzhi Huang.
      Chaperone-mediated autophagy (CMA) is a selective autophagic process essential for maintaining cellular quality and responding to stress. Dysregulation of the CMA pathway is increasingly recognized in various cancers, yet the mechanisms behind CMA hyperactivation in cancer cells remain unclear. Here, we show that CMA is upregulated in patient-derived glioblastoma stem cells (GSCs), indicated by a significant increase in the lysosomal abundance of the CMA receptor, lysosome-associated membrane protein 2 A (LAMP2A). This increase results from MST4-mediated phosphorylation of LAMP2A, enhancing its stability and promoting homotrimer formation while inhibiting degradation by Cathepsin A. CMA supports GSC proliferation and self-renewal by activating mTORC1 through the selective degradation of its negative regulators, TSC1 and TSC2. Additionally, CMA is involved in epigenetic silencing of the cGAS-STING pathway, promoting tumor immune escape via lysosomal degradation of the DNA demethylase TET3. Inhibition of CMA synergizes with immune checkpoint therapy in glioblastoma models, highlighting a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-67119-3
  9. Alzheimers Dement. 2025 Dec;21(12): e70977
    Proteomic analysis links truncated tau to lysosome motility, autophagy, and endo-lysosomal dysfunction.
    Despoina Goniotaki, Maximilian Hausherr, Steven Lynham, Ayushin Ale, George Chennell, Stefania Marcotti, Katrin Marcus, Wendy Noble, Diane P Hanger, Graham Fraser, Deepak P Srivastava.
       INTRODUCTION: Tauopathies involve progressive accumulation of abnormal tau species that disrupt the autophagy-lysosomal pathway (ALP), critical for degrading intracellular macromolecules and aggregates, leading to toxicity and cell death. This study examines how overexpression of the N-terminally truncated Tau35 protein affects proteolytic pathways, including autophagy and endo-lysosomal processes.
    METHODS: Using the Tau35 mouse model and SH-SY5Y human neuroblastoma cells stably expressing Tau35 or full-length tau, we assessed protein degradation and lysosomal function via Western blotting, proteomics of lysosome-enriched brain fractions, cathepsin activity assays, endocytosis/proteolysis assays, and live-cell imaging using LysoTracker.
    RESULTS: We identified early endo-lysosomal alterations associated with Tau35 expression, including increased endocytosis, disrupted autophagic flux, proteolytic impairment, and lysosomal motility defects.
    DISCUSSION: These findings extend previous research by elucidating Tau35-induced dysfunction in intracellular degradation systems and offer mechanistic insight into tauopathy progression. This work provides a foundation for developing targeted therapies to restore acidification, proteostasis, and lysosomal function in tauopathies.
    HIGHLIGHTS: Tau35, an N-terminally truncated tau fragment, disrupts proteolytic pathways: We show that Tau35 overexpression leads to significant alterations in autophagy and endo-lysosomal function. Endo-lysosomal dysfunction is an early pathological event: Our findings demonstrate early-stage increases in endocytosis, impaired proteolytic activity, altered autophagic flux, and disrupted lysosomal motility in Tau35-expressing models. In vivo and in vitro models confirm consistent pathogenic signatures: Parallel studies in a Tau35 mouse model and SH-SY5Y cells reveal converging cellular and molecular dysfunctions. Lysosome-enriched proteomics reveals novel pathway alterations: Proteomic profiling of lysosomal fractions identifies Tau35-specific protein dysregulation contributing to disease pathology. Mechanistic insights into tauopathy progression: These results provide a mechanistic understanding of how truncated tau species contribute to neuronal dysfunction, offering a rationale for targeting endo-lysosomal pathways in therapeutic development.
    Keywords:  LysoTracker; SH‐SY5Y cells; Tau35; autophagy‐lysosomal pathway; endocytosis; live‐cell imaging; mice; proteolysis; proteomics; tauopathies
    DOI:  https://doi.org/10.1002/alz.70977
  10. Redox Biol. 2025 Dec 12. pii: S2213-2317(25)00486-0. [Epub ahead of print]89 103973
    NoxO1 promotes endosome formation and reduces intracellular vesicle processing.
    Maureen Hebchen, Falk Herwig, Tim Schader, Manuela Spaeth, Niklas Müller, Katrin Schröder.
      NADPH oxidase organizer 1 (NoxO1) is known as a scaffold cytoplasmic subunit of the reactive oxygen species (ROS) forming Nox1 complex. We previously identified an interaction between NoxO1 and Erbin, a cytosolic scaffold protein that associates with Epidermal Growth Factor Receptor (EGFR), but its ROS-independent roles remain poorly understood. Here, we demonstrate that NoxO1 overexpression remodels the endolysosomal system by expanding early endosomes and lysosomes. A calibrated six-compartment ordinary differential equation model of EGFR trafficking predicts a slowed down intracellular trafficking: NoxO1 overexpression increased internalization rates by 14 % while reducing degradative sorting by 48 %, lysosomal transfer by 24 %, and final degradation by 41 %. Using fluorescent cargo (EGF and BSA), we confirmed enhanced internalization and cargo accumulation in lysosomes, supporting the idea of prolonged lysosomal retention in NoxO1 overexpressing cells. Mechanistically, NoxO1 activated transcription factor EB (TFEB), the master regulator of lysosomal biogenesis, in an Erbin-dependent but ROS independent manner. Proximity ligation assays revealed spatial association of NoxO1, Erbin, EGFR, and TFEB, suggesting a multi-protein regulatory complex. Genetic ablation of Erbin abolished NoxO1-induced increases in early endosome (EEA1) and lysosome (LAMP1) markers, confirming Erbin's essential role. In conclusion, via its interaction with Erbin NoxO1 promotes activation of TFEB, contributes to lysosome formation while delaying cargo degradation.
    Keywords:  EGFR; Endosomal trafficking; Erbin; Lysosome biogenesis; NoxO1; TFEB
    DOI:  https://doi.org/10.1016/j.redox.2025.103973
  11. J Exp Med. 2026 Mar 02. pii: e20250535. [Epub ahead of print]223(3):
    FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
    Liling Xu, Maria Bottermann, Paula M Villavicencio, John Warner, Stephanie R Weldon, Zhenfei Xie, Andrew Filby, Xiaotie Liu, Ian G Ganley, Alison E Ringel, Usha Nair, Facundo D Batista.
      Little is known about the role of autophagy in the human humoral immune system. Here, we found that in B cells, genetic ablation of FIP200, a mammalian metabolic sensor that regulates autophagy in response to a range of stimuli, led to diminished humoral immune responses in mice. FIP200-deficient B cells displayed decreased differentiation into plasma cells, as well as mitochondrial dysfunction, alterations in heme biosynthesis, and significant cell death. Notably, the addition of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming.
    DOI:  https://doi.org/10.1084/jem.20250535
  12. Biochim Biophys Acta Gen Subj. 2025 Dec 16. pii: S0304-4165(25)00142-4. [Epub ahead of print] 130897
    Spermidine deficiency induces BNIP3/LC3B-mediated mitophagy in the salivary glands of accelerated aging mice.
    Nguyen Khanh Toan, Manh Dat Duong, Nguyen Duy Phu, Le Viet Thanh, Sang-Gun Ahn.
      Aging is associated with mitochondrial dysfunction and altered autophagic processes, particularly in secretory organs such as the salivary glands. In this study, we investigated metabolic changes and their interactions with mitophagy in primary salivary gland cells (PSGCs) from klotho-deficient (kl-/-) mice, a model of accelerated aging. We observed a significant reduction in both mitochondrial number and mitochondrial DNA copy number in the PSGCs of kl-/- mice compared with those of wild-type (WT) controls. In contrast, lysosomal abundance was markedly increased in PSGCs from kl-/- mice. Moreover, the expression of the autophagy marker LC3B was significantly upregulated in kl-/- PSGCs, and the expression of the mitophagy markers BNIP3 and NIX increased. Our metabolomic profiling revealed disrupted spermidine biosynthesis in the salivary glands of kl-/- mice. Interestingly, spermidine treatment in kl-/- PSGCs increased the number of mitochondria and suppressed mitophagy, as indicated by the reduced expression of BNIP3 and LC3B. Conversely, in WT PSGCs, spermidine induced the expression of autophagy and mitophagy markers, namely, BNIP3 and LC3B. These findings suggest that accelerated aging in mice impairs mitochondrial homeostasis and alters autophagy/mitophagy pathways in salivary gland cells, potentially through the dysregulation of spermidine metabolism. Our results provide insight into the molecular mechanisms of aging in salivary glands and reveal the potential role of polyamine metabolism in maintaining mitophagy during aging.
    Keywords:  Aging; Mitochondria; Mitophagy; Salivary glands; Spermidine
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130897
  13. Transl Neurodegener. 2025 Dec 16. 14(1): 69
    Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.
    Alexander Veh, Melissa Ewald, Vinicius da Cruz Neris Geßner, Neha Jadhav Giridhar, Amy-Jayne Hutchings, Christian Stigloher, Beyenech Binotti, Katrin Gertrud Heinze, Patrick Lüningschrör.
       BACKGROUND: Atg9-containing vesicles are enriched in synapses and undergo cycles of exo- and endocytosis similarly to synaptic vesicles, thereby linking presynaptic autophagy to neuronal activity. Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease (MND), which leads to impaired synaptic integrity and function. Here, we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice, an MND model with defective presynaptic autophagy.
    METHODS: To characterize the vesicle accumulations in Plekhg5-deficient mice, we performed immunohistochemical staining, electron microscopy, and super-resolution imaging. Following voluntary running wheel exercise, we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach. Additionally, we analyzed the motor performance of the animals by measuring their grip strength. To assess changes in the autophagic flux upon physical exercise in vivo, we utilized mRFP-GFP-LC3 expressing mice. The presence of Atg9-containing vesicle clusters in SOD1G93A was analyzed to examine the relevance of this pathological feature in a second MND model.
    RESULTS: We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice, which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice. However, physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal. In line with these findings, short-term voluntary exercise triggered motoneuron autophagy in young but not old mice. Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND, we also found Atg9-containing vesicle accumulations in SOD1G93A mice, a well-established ALS model. Strikingly, physical exercise in presymptomatic SOD1G93A mice resulted in a reduction of the vesicle accumulations.
    CONCLUSIONS: Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.
    Keywords:  Atg9; Autophagy; Axon; Motoneuron disease; Physical exercise; Plekhg5
    DOI:  https://doi.org/10.1186/s40035-025-00524-2
  14. J Clin Invest. 2025 Dec 16. pii: e195031. [Epub ahead of print]
    FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth.
    Jianfang Gao, Jina Qing, Xianglong Li, Yuxuan Luo, Lingwen Huang, Hongxia Li, Huan Zhang, Jiao Zhang, Pei Xiao, Jinsong Li, Tingting Li, Shanping He.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a master controller of cell growth and its dysregulation is associated with cancer. KICSTOR, a complex comprising KPTN, ITFG2, C12orf66, and SZT2, functions as a critical negative regulator of amino acid-induced mTORC1 activation. However, the regulatory mechanisms governing KICSTOR remain largely unclear. In this study, we identify FBXO2 as a key modulator of amino acid-dependent mTORC1 signaling. Mechanistically, FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at lysine residues 49, 67, 262, and 265. FBXO2-mediated KPTN ubiquitination disrupts its interaction with ITFG2 and SZT2, while enhancing its interaction with C12orf66, thereby impairing the ability of KICSTOR to recruit the GATOR1 complex to the lysosomal surface. Notably, FBXO2 protein levels are substantially upregulated in liver cancer patients and FBXO2-mediated KPTN ubiquitination facilitates the progression of hepatocellular carcinoma (HCC). These results reveal a key regulatory mechanism of the mTORC1 signaling and highlight FBXO2 and KPTN ubiquitination as therapeutic targets for HCC treatment.
    Keywords:  Cell biology; Liver cancer; Oncology; Signal transduction; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI195031
  15. Nutr Res Rev. 2025 Dec 17. 1-44
    Distinct Roles of Urolithin A and Spermidine in Mitophagy and Autophagy: Implications for Dietary Supplementation.
    Pavel Borsky, Drahomira Holmannova, Ondrej Soukup, Zdenek Fiala, Tereza Maresova, Michaela Hanzlova, Tom Philipp, Lenka Borska.
      The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/ Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. On the other hand, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5' AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signaling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction, and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-aging effects.
    Keywords:  Autophagy; Mitophagy; Spermidine; Supplement; Urolithin A
    DOI:  https://doi.org/10.1017/S0954422425100292
  16. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00390-3. [Epub ahead of print]32(12): 1439-1441
    Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
    Chih-Yao Chung, Kritarth Singh, Brigida R Pinho, Jorge M A Oliveira, Michael R Duchen.
      Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.010
  17. Dermatol Surg. 2025 Sep;51(9S): S33-S37
    RLX-201, a Novel mTORC1 Inhibitor With Potential to Promote Skin Longevity and Cellular Health.
    Manpreet Randhawa, Krzysztof Bojanowski, Teresa Ferraro, Zhen Fang Huang Cao, Doris Day, Rahul C Mehta.
       BACKGROUND: mTORC1 activity drives characteristic phenotypes of senescence, contributing to extracellular matrix breakdown and accelerate aging phenotypes. Targeting mTORC1 without disrupting mTORC2 offers a promising strategy for skin longevity.
    OBJECTIVE: To assess age-related mTORC1 activity in fibroblasts and evaluate RLX-201, a novel mTOR inhibitor, and its effects on mTORC1 and mTORC2 activity in skin fibroblasts.
    METHODS: Human dermal fibroblasts from young (23 years) and older (56 years) donors were analyzed for total and phosphorylated RPS6 by immunocytochemistry and automated western blotting. RLX-201's effects on mTORC1 (p70S6K) and mTORC2 (pAKT Ser473) were measured using HTRF assays.
    RESULTS: Older fibroblasts showed increased p-RPS6 levels, indicating higher basal mTORC1 activity. RLX-201 selectively inhibited mTORC1 without suppressing mTORC2, unlike high-dose rapamycin, which reduced both. RLX-201 treatment appears to alter the morphology of fibroblasts to a younger phenotype.
    CONCLUSION: mTORC1 hyperactivity is a key feature of aging fibroblasts and contributes to skin aging. RLX-201 enables selective mTORC1 inhibition while preserving mTORC2 activity, supporting its potential to counteract aging-related skin dysfunction and promote skin longevity. Treatment with RLX-201 can rejuvenate the fibroblasts increasing their functionality.
    DOI:  https://doi.org/10.1097/DSS.0000000000004805
  18. bioRxiv. 2025 Nov 26. pii: 2025.11.24.690233. [Epub ahead of print]
    cAMP promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.
    Saumya Bhatt, Mohammad Ali Abbas Zaidi, Nicholas Woods, Cody N Rozeveld, Micah B Schott.
      Cyclic adenosine monophosphate (cAMP) signaling is a major stimulus for lipid and glucose catabolism, yet catabolic processes like these can also coordinate with lysosome-dependent degradation. However, the impact of cAMP signaling on lysosomal dynamics remains unclear. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is regulated by stimulus-dependent nuclear-cytoplasmic shuttling through a variety of phosphorylation events. Here, we find that elevating intracellular cAMP with forskolin and IBMX induces rapid nuclear import of TFEB-GFP within 30 minutes and coincides with a transient upregulation of TFEB target lysosome genes. By 8 hours, TFEB returns to the cytoplasm, accompanied by transcriptional downregulation. Inhibition of cAMP-dependent protein kinase A (PKA) using H89 did not block nuclear import but unexpectedly caused sustained nuclear accumulation, indicating that PKA promotes TFEB nuclear export. Consistent with this, phosphoproteomic profiling revealed increased phosphorylation of a PKA-consensus motif (RRx S) during the export phase. These findings suggest that cAMP-PKA signaling plays a novel role in temporally "tuning" lysosomal gene expression by regulating TFEB nuclear-cytoplasmic shuttling.
    Summary: This study reveals that cAMP signaling dynamically regulates TFEB subcellular localization, promoting transient, calcium-dependent nuclear import as well as downstream, PKA-dependent export and phosphorylation at serines 466/467. These findings uncover a novel mechanism by which cAMP stimulation fine-tunes lysosomal gene expression by regulating TFEB nuclear import and export.
    DOI:  https://doi.org/10.1101/2025.11.24.690233
  19. Protoplasma. 2025 Dec 17.
    Physcomitrium patens: an emerging model for autophagy study.
    Md Arif Sakil.
      Physcomitrium patens (formerly Physcomitrella patens), a model moss species, has emerged as an invaluable system for studying autophagy in plants. This review highlights the unique advantages of P. patens for autophagy research, including its efficient homologous recombination in mitotic cells, simple body plan, haploid-presiding life cycle, and accessibility to microscopic observation. I discuss recent advances in understanding autophagy mechanisms in P. patens, particularly focusing on the role of core autophagy-related (ATG) genes in growth, development, stress responses, and cell death. The characterization of autophagy-deficient mutants revealed unexpected roles of autophagy in promoting cell death under oxidative stress and desiccation, in contrast with classical survival functions. I also examine the conservation and divergence of the autophagy machinery between mosses and vascular plants, emphasizing how P. patens bridges evolutionary gaps in our understanding of plant autophagy. Finally, I outline future perspectives on the use of this model system to address fundamental questions about selective autophagy, autophagosome dynamics, and the integration of autophagy with developmental programs.
    Keywords:  ATG genes; Autophagic cell death; Autophagy; Bryophyte; Model organism; Physcomitrium patens; Stress response
    DOI:  https://doi.org/10.1007/s00709-025-02148-9
  20. Sci Adv. 2025 Dec 19. 11(51): eaed8002
    GPNMB, LRRK2, and lysosome exocytosis in Parkinson's.
    Suzanne R Pfeffer.
      When two genes linked to increased Parkinson's risk converge on a lysosome, LRRK2 mutation enhances lysosomal release of soluble GPNMB potentially contributing to synuclein pathology.
    DOI:  https://doi.org/10.1126/sciadv.aed8002
  21. Physiol Res. 2025 Dec 15. 74(6): 891-907
    Pathogenic Role of mTOR Signaling in Cardiometabolic Disease: Implications for Heart, Liver, and Kidney Dysfunction.
    M Arora, J Zicha, I Vaněčková.
      Cardiometabolic diseases (CMDs), which include hypertension, atherosclerosis, chronic kidney disease, type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity, significantly affect the heart, liver, and kidneys. A key player in the pathogenesis of these diseases is the serine-threonine kinase enzyme mTOR (mammalian target of rapamycin), which affects cellular metabolic processes through its signaling. mTOR is composed of two separate complexes: mTORC1 and mTORC2. Both complexes are essential for cardiac development and pathological stress responses. Constant activation of mTORC1 can be harmful, contributing to cardiac hypertrophy and remodeling, which can lead to heart failure. Conversely, mTORC2 supports the survival and function of cardiomyocytes during stressful situations. In the liver, mTOR signaling plays a crucial role in lipid metabolism and insulin sensitivity, both of which are affected by diet. Activation of mTORC1 in hepatocytes can cause hepatic steatosis, dyslipidemia, and insulin resistance, which are characteristics of metabolic dysfunction and type 2 diabetes mellitus (T2DM). Conversely, mTORC2 protects against steatohepatitis. Reducing mTORC1 activity in the liver improves these metabolic disturbances. Altered mTOR signaling may result from abnormal feeding states, which affect the metabolic and physiological functions of the liver and kidneys. In diabetic nephropathy, overstimulation of mTORC1 in the kidneys leads to hypertrophy, proteinuria, and eventual loss of renal function. Meanwhile, mTORC2 participates in renal ion transport. Treatment with mTOR inhibitors has ameliorated renal dysfunction in preclinical models of diabetic kidney dysfunction and the Dahl S model of salt hypertension. This review emphasizes the critical role of mTOR in the pathophysiology of cardiometabolic diseases in major organs and models. Targeting mTOR signaling pathways is a promising approach to mitigate the adverse effects of CMD on the heart, liver, and kidneys. Key words Cardiometabolic disease " mTOR " Dyslipidemia " Salt sensitive " Hypertension.
  22. Biochim Biophys Acta Gene Regul Mech. 2025 Dec 16. pii: S1874-9399(25)00056-2. [Epub ahead of print]1869(1): 195131
    Autophagy-related genes and encoded proteins' prognostic significance in various cancer types: A molecular perspective.
    Eman A Amr, Ola A El-Feky, Nahla E El-Ashmawy, Eman G Khedr.
      Autophagy is a degradative process for recycling and breaking down cellular components, with several context-dependent functions in the development of tumors and resistance to therapy. Numerous clinical trials aiming to target autophagy in different tumors have been initiated as indicated by encouraging results from diverse preclinical investigations. Research on the connection between autophagosomes and the prognosis of different malignancies is now underway. The autophagy machinery itself may serve as a source of biomarkers for this purpose. Numerous research studies have established the association between autophagy-related genes (ATGs) and proteins (Atgs) in diverse types of cancer. Nonetheless, the outcomes of this association are still uncertain and the validation of reliable autophagy-related biomarkers is still lagging behind, owing to the paradoxical roles of autophagy in tumor biology and the scarcity of primary research studies. Herein, we explore recent developments, issues, and trends in the evaluation of clinically significant ATGs' and their encoded proteins' biomarker potential in human malignancies.
    Keywords:  Apoptosis; Autophagy; Biomarkers; Cancer; Prognosis
    DOI:  https://doi.org/10.1016/j.bbagrm.2025.195131
  23. Cell Stress Chaperones. 2025 Dec 16. pii: S1355-8145(25)00084-7. [Epub ahead of print] 100139
    Protein quality control: from molecular mechanisms to aging and disease - EMBO workshop, May 18-23, 2025, Hersonissos, Greece.
    Claes Andréasson, Anat Ben-Zvi.
      Cells safeguard the functionality of the proteome using complex pathways of protein quality control. The centerpiece of this proteostasis network is a large set of molecular chaperones and proteases that impact the entire lifespan of proteins by controlling protein folding and degradation. Dysfunction of the proteostasis network is associated with many diseases and age-associated functional decline of neurons, including Alzheimer's and Parkinson's diseases, as well as several motor neuron diseases. The 2025 EMBO workshop "Protein quality control: from molecular mechanisms to aging and disease" gathered the large and interdisciplinary community of researchers that study protein quality control, from its fundamental molecular mechanisms via higher order organization in organisms to its impact on and use in the medical field. Here we summarize the workshop and report research findings.
    Keywords:  Aggregation, Autophagy; Chaperone; Folding, Protein quality control; Proteostasis; Stress ubiquitin-proteasome system (UPS)
    DOI:  https://doi.org/10.1016/j.cstres.2025.100139
  24. Metab Brain Dis. 2025 Dec 17. 41(1): 4
    Unveiling the neuroprotective power: the role of autophagy in remote ischemic conditioning.
    Vinay Tyagi, Mohd Hanifa, Bivek Bajgai, Deepika Choudhary, Anjana Bali.
      A stroke is a sudden neurological impairment caused by damage to the vascular system of the central nervous system. Remote ischemic conditioning (RIC) has emerged as a promising therapeutic strategy, gaining attention for its potential to provide neuroprotection against cerebral strokes in both clinical and preclinical settings. Recent research highlights autophagy as a key element of RIC-induced neuroprotection during cerebral ischemia. Preclinical studies suggest that RIC effectively modulates key signalling pathways, including AKT/GSK-3β, AKT-Bcl-2, Transcription Factor EB (TFEB), PINK1/Parkin, and AMPK. This modulation promotes autophagy and enhances the neuroprotective effects of RIC. Furthermore, evidence from preclinical studies indicates that RIC significantly reduces inflammation, oxidative stress, and infarct size while modulating apoptotic signalling through the activation of autophagy. This article highlights recent research that illustrates the complex interplay between RIC-induced autophagy and neuroprotection, indicating that targeting these pathways may offer innovative therapeutic approaches for treating ischemic stroke.
    Keywords:  Autophagy; Ischemia; Neuroprotection; Remote ischemic preconditioning; Stroke
    DOI:  https://doi.org/10.1007/s11011-025-01765-w
  25. NPJ Aging. 2025 Dec 19.
    Age-related nigral downregulation of the Parkinson's risk factor FAM49B primes human microglia for inflammaging.
    Jacqueline Martin, Guan-Ju Lai, Christopher Y Park, Colista West, Trevor Van Brunt, Samarah Ahmed, Saheed Lawal, Maya Dickson, Taylor Russo, Wendy Akmentin, Molly Weiner, Zachary B Hobel, Benjamin Kolisnyk, Joshua L Plotkin, Olga G Troyanskaya, Markus Riessland.
      Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD risk gene FAM49B is critically expressed in microglia of the human SNpc and is downregulated with age and PD. We utilized human and murine microglia cells to demonstrate the role of FAM49B in regulating fundamental microglial functions such as cytoskeletal maintenance, migration, surface adherence, energy homeostasis, autophagy, and, importantly, inflammatory response. Downregulation of microglial FAM49B, as observed in the SNpc of aging individuals, led to significant alterations in these cellular functions, which are associated with increased microglial activation. Thus, our study highlights novel cell-type-specific roles of FAM49B and provides a potential mechanism for susceptibility to neuroinflammation, and reactive gliosis observed in both PD and normal aging.
    DOI:  https://doi.org/10.1038/s41514-025-00296-z
  26. J Biol Chem. 2025 Dec 12. pii: S0021-9258(25)02906-0. [Epub ahead of print] 111054
    Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
    Jiayu Chen, Hairong Zhao, Yuemei Xi, Shanpan Fu, De Xie, Linqian Yu, Qiang Wang, Binyang Chen, Qian Zhang, Mingyan Zhang, Xueling Ye, Mengni Wu, Wanling Que, Shuyi Chen, Yayan Liu, Tetsuya Yamamoto, Hidenori Koyama, Hong Zhao, Jidong Cheng.
      The rising prevalence of hyperuricemia associated with lifestyle changes has been confirmed as an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Mitochondria, as central regulators of lipid metabolism, maintain functional homeostasis through mitophagy, the selective removal of damaged or dysfunctional mitochondria. However, whether and how high uric acid (HUA) induces mitophagy and the mechanistic role of mitophagy in hyperuricemia-induced hepatic lipid metabolism disorders remain to be elucidated. Our study demonstrated that HUA induces hepatic fat accumulation and damaging mitochondria in primary mouse hepatocytes. Simultaneously, mitophagy was activated by HUA, evidenced by upregulated expression and phosphorylation of PINK1 and Parkin, enhanced LC3B-I to LC3B-II conversion, and enhanced TOM20-LC3B immunofluorescence co-localization. In urate oxidase gene knockout (Uox-KO) mice (a model of sustained hyperuricemia), we detected significantly elevated expression of mitophagy-related proteins in liver tissues, accompanied by marked lipid accumulation and inflammatory responses. Further studies demonstrated that HUA upregulates CD36 protein expression. CD36 knockdown alleviated lipid accumulation in primary mouse hepatocytes, whereas PINK1 knockdown exacerbated this effect through further CD36 upregulation. Notably, treatment with the mitophagy activator Urolithin A significantly ameliorated hepatic lipid accumulation and inflammation in Uox-KO mice. These findings demonstrate that the PINK1-Parkin-mediated mitophagy activated by HUA serves as a protective mechanism against HUA-induced hepatic fat accumulation. Our results suggest that mitophagy regulation may represent a novel therapeutic target for HUA-induced hepatic fat accumulation.
    Keywords:  CD36; Hepatic lipid accumulation; Hyperuricemia; Mitophagy; PINK1-Parkin pathway
    DOI:  https://doi.org/10.1016/j.jbc.2025.111054
  27. Circulation. 2025 Dec 18.
    Endothelial Transcription Factor EB Protects Against Doxorubicin-Induced Endothelial Toxicity and Cardiac Dysfunction.
    Wa Du, Madison Ringer, Wei Huang, Darshini Desai, Golam Iftakhar Khandakar, Luis Tron Esqueda, Chenran Wang, Jun-Lin Guan, Richard C Becker, Sakthivel Sadayappan, Guo-Chang Fan, Yigang Wang, Yanbo Fan.
       BACKGROUND: Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell (EC) dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, regulates cardiovascular homeostasis. In the present study, we aimed to test whether endothelial TFEB protects against EC damage and alleviates cardiac dysfunction induced by DOX treatment.
    METHODS: EC-specific TFEB transgenic mice, EC-specific TFEB knockout mice, and their corresponding littermate controls were administered DOX intravenously. Survival curves were generated, and cardiac functions were measured in mice. The effects of TFEB on mitochondrial reactive oxygen species production, autophagic flux, and apoptosis were evaluated in human and mouse cardiac microvascular ECs treated with DOX. RNA sequencing, single-cell RNA sequencing, and chromatin immunoprecipitation with quantitative polymerase chain reaction was performed to dissect molecular mechanisms in DOX-treated ECs in vitro and in vivo. Mice with endothelium-specific deficiency of DAB adaptor protein 2 (Dab2) were subjected to measurement of cardiac function and fibrosarcoma growth under DOX treatment.
    RESULTS: EC-specific TFEB transgenic mice showed significantly reduced mortality and improved cardiac function, together with attenuation of perivascular fibrosis after DOX treatment. By contrast, EC-specific TFEB knockout exacerbated DOX-induced cardiac dysfunction in mice. Furthermore, we observed that TFEB enhanced autophagy and reduced oxidative stress in cardiac microvascular ECs treated with DOX. In addition, TFEB preserved EC barrier integrity, alleviated proinflammatory cytokine release from cardiac microvascular ECs, and maintained the EC-cardiomyocyte communication, contributing to the protective effects of EC TFEB on cardiomyocyte function. Mechanistically, DAB2, a clathrin- and cargo-binding endocytic adaptor protein, was identified as a TFEB target gene in ECs. Accordingly, DAB2 knockdown attenuated the inhibitory effects of TFEB on apoptosis and the secretion of proinflammatory cytokines from cardiac microvascular ECs. In vivo, EC-specific Dab2 deficiency abolished the protective effect of EC TFEB on DOX-induced cardiac dysfunction.
    CONCLUSIONS: Taken together, endothelial TFEB protects against EC damage and cardiac dysfunction, constituting a potential target for treating cardiotoxicity induced by DOX. Our study provides new mechanistic insights into cardiotoxicity associated with chemotherapy.
    Keywords:  DAB2; cardiotoxicity; chemotherapy; endothelial toxicity; transcription factor EB
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.071774
  28. Stem Cell Res Ther. 2025 Dec 13.
    Human umbilical cord-derived mesenchymal stem cells ameliorate non-alcoholic fatty liver disease via activating TFEB-mediated autophagy in male mice.
    Huina Zhang, Peng Liu, Yaxuan Deng, Li Wu, Orion Fan, Yanling Cui, Chunxue Zhang, Wenmin Zhu, Yi Eve Sun, Chuwen Lin, Congrong Wang.
       BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid accumulation in hepatocytes and defective autophagy has been implicated in its pathogenesis. Human umbilical cord-derived MSCs (hUC-MSCs) have shown therapeutic potential in treating NAFLD, while underlying molecular mechanisms remained largely unknown.
    METHODS: Male C57BL/6J mice fed a choline-deficient high fat diet (CD-HFD) and HepG2 cells exposed to palmitic acid/oleic acid were established as in vivo and in vitro models of NAFLD, respectively. Both models were subjected to treatment with human umbilical cord-derived MSCs (hUC-MSCs). Lipid content, proinflammatory cytokines, fibrosis markers and the hepatic transcriptome were assessed to determine the effect of hUC-MSCs.
    RESULTS: Here, hUC-MSCs decreased hepatic lipid content and alanine aminotransferase/aspartate aminotransferase levels, as well as attenuated inflammation and fibrosis in choline-deficient high-fat diet (CD-HFD)-induced NAFLD mice. Mechanistically, hUC-MSCs restored impaired autophagic flux and mitigated liver steatosis through the AMPK-mTOR-TFEB pathway in both NAFLD mice and oleic acid/palmitic acid-induced "fatty" HepG2 cells. Of note, hUC-MSCs have been found to promote nuclear translocation of TFEB in PA/OA-induced HepG2 cells. Additionally, TFEB knockdown partially attenuated the effect of hUC-MSCs on enhancing autophagy and lipid metabolism in vitro.
    CONCLUSIONS: This study suggests that hUC-MSCs represent a potential therapeutic approach to treating NAFLD through activating TFEB-mediated autophagy.
    Keywords:  Autophagy; NAFLD; Transcription factor EB; hUC-MSCs
    DOI:  https://doi.org/10.1186/s13287-025-04855-9
  29. Mov Disord. 2025 Dec 17.
    Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation-Resistant SPAST Mutation.
    Dingyi Zhang, Yang Hu, Jianhe Guo, Dongmei Wu, Yifan Zhang, Lingzi Yang, Yuxi Wang, Nong Xiao, Jinhua Fan, Yanling Dong, Min Zhong, Tongfei Liu.
       BACKGROUND: Hereditary spastic paraplegias (HSPs) are monogenic neurodegenerative disorders, and SPAST mutations causing spastic paraplegia type 4 (SPG4) represent the most common form of HSP. SPAST mutations elevate SPASTIN protein levels beyond haploinsufficiency, but the mechanisms and downstream consequences are unclear.
    METHODS: We identified a de novo SPAST missense variant (p.I344E) in a young Chinese female with SPG4. Wild-type (WT) and mutant (I344E/K) SPAST constructs were expressed in HEK293 for biochemical and functional assays including cycloheximide chase, ubiquitination analysis, and immunofluorescence. Leveraging somatic cell reprogramming and CRISPR-based gene editing, we generated patient-derived induced pluripotent stem cells (iPSCs) and their isogenic controls. Both lines were differentiated into cerebral organoids.
    RESULTS: I344E/K-SPASTIN exhibited markedly higher steady-state levels than WT-SPASTIN owing to impaired ubiquitin-proteasome-mediated degradation; the I344E variant showed the greatest accumulation. Mutant SPASTIN mislocalized in cells, displayed diminished microtubule-severing activity, and elevated acetylated tubulin-phenotypes that were rescued by overexpression of WT-SPASTIN. In patient cerebral organoids, the I344E mutation led to increased p62/SQSTM1 aggregates, reduced autophagic flux, and enhanced neuronal death. Rapamycin restored autophagy, decreased p62 levels, and reduced cell death.
    CONCLUSIONS: Our study provides evidence linking autophagy dysfunction to SPG4 pathogenesis and demonstrates that the I344E mutation acts through a gain-of-function mechanism. These findings challenge the prevailing haploinsufficiency model and implicate autophagy modulation as a potential therapeutic strategy for SPG4 and possibly other HSPs. © 2025 International Parkinson and Movement Disorder Society.
    Keywords:  SPAST; autophagy; hereditary spastic paraplegia; iPSC; organoid
    DOI:  https://doi.org/10.1002/mds.70150
  30. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  31. Future Med Chem. 2025 Dec 16. 1-17
    Targeting autophagy kinases: from mechanisms to therapy with novel small molecules.
    Linlin Deng, Linwei Li, Yue Li, Ting Ma, Shaojie Liang, Erkang Tian.
      Autophagy is an evolutionarily conserved process in eukaryotic cells that degrades and recycles intracellular macromolecules and damaged organelles. It is closely related to a variety of physiological and pathological processes. Research on autophagy has become a current hotspot, with protein kinases regarded as crucial components that play essential roles throughout this process. During autophagy, diverse autophagy-related protein kinases continuously regulate different stages. Protein kinases are critical in signal transduction and the regulation of most cellular processes. Therefore, autophagy-associated protein kinases represent potential therapeutic targets for human diseases, and corresponding small-molecule compounds may provide promising therapeutic strategies. This review summarizes the current progress in autophagy research, with a focus on small-molecule drugs that influence autophagy-related kinases and their association with diseases.
    Keywords:  Autophagy; modulators; protein kinases; small molecule compounds; targeted therapy
    DOI:  https://doi.org/10.1080/17568919.2025.2602421
  32. Stem Cell Res. 2025 Dec 12. pii: S1873-5061(25)00237-5. [Epub ahead of print]90 103887
    CRISPR/Cpf1-mediated editing of PINK1 in induced pluripotent stem cells.
    Roohallah Ghodrat, Haribaskar Ramachandran, Barbara Hildebrandt, Stephanie Binder, Andrea Rossi, Andreas S Reichert.
      The PTEN induced kinase 1 (PINK1) gene is crucial for mitophagy and mitochondrial quality control. Mutations in the PINK1 gene are associated with several neurological disorders. To decipher the role of PINK1-mediated mitophagy in human induced pluripotent stem cells (hiPSCs) and in their differentiated counterparts, we used CRISPR/Cpf1 and generated a human iPSC line with homozygous out-of-frame deletions by targeting exon 6 of the PINK1 gene. The generated homozygous PINK1 mutant cell line showed normal cell morphology, genomic stability, and expression of classical stem cell markers. Furthermore, the cells can be differentiated efficiently into the three germ layers.
    DOI:  https://doi.org/10.1016/j.scr.2025.103887
  33. Mol Cells. 2025 Dec 11. pii: S1016-8478(25)00132-3. [Epub ahead of print] 100308
    Multilayered regulation of longevity in Caenorhabditis elegans.
    Dajeong Bong, Hyunwoo C Kwon, Seung-Jae V Lee.
      Aging in Caenorhabditis elegans is regulated by evolutionarily conserved pathways that coordinate cellular maintenance and systemic homeostasis. Here, we review recent advances on four major longevity regimens including reduced insulin/insulin-like growth factor 1 signaling (IIS), dietary restriction (DR), mild inhibition of mitochondrial respiration, and germline deficiency. Each longevity-promoting regimen enhances protein and RNA quality control, metabolic remodeling, and stress resistance to delay functional declines with age. Reduced IIS strengthens proteostasis and RNA surveillance. DR remodels metabolism and activates autophagy. Mild mitochondrial inhibition elicits adaptive redox signaling and quality control responses. Germline deficiency links reproductive cues to somatic maintenance. We highlight that longevity arises from integrated regulation of transcriptional, metabolic and inter-tissue signaling networks. Our review will provide valuable insights obtained from C. elegans into the conserved mechanisms of aging, facilitating the development of interventions that promote healthy longevity in humans.
    Keywords:  Caenorhabditis elegans; dietary restriction; germline deficiency; insulin/IGF-1 signaling; longevity; mild mitochondrial inhibition
    DOI:  https://doi.org/10.1016/j.mocell.2025.100308
  34. Exerc Immunol Rev. 2025 ;31 19-26
    Less Inflammatory Debris, Improved Immunity from Immune Detox: A New Perspective on the Benefits of Exercise in Chronic Disease.
    Asghar Abbasi, William Stringer.
      The immunological benefits of exercise are commonly attributed to its immune-boosting effects such as the release of exercise-induced factors (e.g., exerkines) and activation of anti-inflammatory molecules. However, this may not fully explain its benefits in chronic inflammatory conditions. We propose a complementary view whereby exercise potentially functions as a biological detoxifier by removing harmful immunological debris such as damage-associated molecular patterns (DAMPs), senescent cells, dysfunctional mitochondria and pro-inflammatory extracellular vesicles (EVs) that drive chronic immune activation. We highlight key mechanisms by which exercise may reduce or remove these harmful signals, including autophagy and mitophagy activation, enhanced efferocytosis, reduced senescence burden, and modulation of EV cargo. This "immune detox" model may help explain the clinical benefits of exercise in conditions where the immune system is overactivated, not deficient. It shifts the narrative from immune boosting to restoring immune balance, and could have potentially important implications for biomarker discovery and personalized exercise prescriptions in chronic disease.
  35. Folia Med Cracov. 2025 Sep 30. 65(3): 173-183
    A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.
    Kamila Żur-Wyrozumska.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.
    MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.
    CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.
    DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.
    CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.
    Keywords:  NF-κB; Nrf2; SQSTM1 mutation; amyotrophic lateral sclerosis (ALS); autophagy; neuroinflammation; p62; precision medicine
    DOI:  https://doi.org/10.24425/fmc.2025.156692
  36. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  37. Stem Cell Reports. 2025 Dec 18. pii: S2213-6711(25)00348-0. [Epub ahead of print] 102744
    Autophagy is required for the development and functionality of lacrimal gland-like organoids.
    Gamze Kocak, Miriam E Korsgen, Leticia F Amores, Congxin Sun, Merve Ceylan, Asmaa Ghazwani, Merve Kandirici, Malgorzata Zatyka, Elena Seranova, Animesh Acharjee, Timothy Barrett, Bayram Yuksel, Adil Mardinoglu, Sinan Güven, Sovan Sarkar.
      Lacrimal glands (LGs) serve as pivotal exocrine glands crucial for protecting the ocular surface. Dysfunction in LG cell composition or secretion is implicated in dry eye disease (DED). While autophagy plays a vital role in tissue homeostasis in many organs, how it affects LG development and secretory function is not known. Here, we have undertaken a genetic study by utilizing autophagy-deficient human embryonic stem cells (hESCs) and differentiating them into LG-like organoids. Autophagy-deficient LG-like organoids exhibited improper development and secretion, along with increased protein aggregation, proliferation, and cell death. These phenotypes were associated with an accumulation of PAX6, a transcription factor crucial for brain and eye development, which we identified as an autophagy substrate. Pharmacological interventions with nicotinamide mononucleotide (NMN) and melatonin were able to rescue the cellular dysfunction in autophagy-deficient LG-like organoids. Together, our study highlights the role of autophagy in LG along with potential therapeutic interventions for DED.
    Keywords:  NMN; PAX6; SEAM; autophagy; cell death; development; differentiation; hESC; lacrimal gland; organoid
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102744
  38. Future Med Chem. 2025 Dec 19. 1-12
    Autophagosome degraders: a novel therapeutic strategy with broad application potential in human diseases.
    Wei-Fang Zuo, Xinyi Huang, Cheng Peng, Bo Han, Qian Zhao.
      Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverages the autophagy-lysosome pathway for the clearance of challenging substrates that often exceed proteasomal capacity. These substrates include large protein aggregates, multi-protein complexes, and even entire organelles. This review synthesizes key advances in the development of autophagy-based degraders since 2022, highlighting their therapeutic potential through exemplar applications. We discuss their utility in oncology, neurodegenerative disorders, and inflammatory/cardiometabolic diseases. These novel modalities have demonstrated potent, selective, and durable substrate elimination in vivo, successfully overcoming resistance mechanisms associated with traditional occupancy-driven inhibition. Finally, we summarize the general workflow for developing autophagy-based degraders, outline the current challenges and future directions in this field, and aim to promote fundamental mechanistic studies and innovative medicinal chemistry research, thereby accelerating the clinical translation of autophagy-targeting degraders for the treatment of various human diseases.
    Keywords:  Autophagy-lysosomal pathway; autophagosome degraders; cancer; cardiometabolic disorders; neurodegenerative diseases; targeted protein degradation
    DOI:  https://doi.org/10.1080/17568919.2025.2605014
  39. Commun Biol. 2025 Dec 18.
    Inhibition of STING-mediated antiviral innate immunity activation by CD97 via modulation of ER-phagy.
    Huasong Chang, Rukun Yang, Wenjing Qi, Peili Hou, Aibiao Xiang, Xiaoyu Liu, Ran Kang, Hongmei Wang, Hongbin He.
      Endoplasmic reticulum (ER) autophagy (ER-phagy) is a vital homeostatic process triggered by multiple signals and plays a crucial role in regulating innate immunity and viral replication. However, the mechanisms by which host proteins utilize ER-phagy to regulate innate immune response during viral infection remains largely unclear. Here, we uncover the regulatory crosstalk between innate immune adapter, ER retention protein Stimulator of Interferon Genes (STING), and the G protein-coupled receptor ADGRE5/CD97 (Cluster of Differentiation 97). Our results demonstrate that CD97 suppresses the STING-mediated type-I interferon (IFN-I) response against DNA virus and cytosolic DNA, thereby promoting herpes simplex virus type 1 (HSV-1) replication in both cells and mice. CD97 facilitates the recruitment of the ER-phagy receptor, FAM134B (family with sequence similarity 134, member B), to initiate ER-phagy, resulting in the degradation of STING subsequent to DNA virus infection. Furthermore, Cd97-deficient mice exhibit higher IFN-I response and greater resistance to HSV-1 infection. Additionally, our findings reveal that inhibiting CD97 with sanguinarine effectively disrupts HSV-1 replication. These findings shed light on the role of CD97 in the innate immune response against DNA virus infections and offer valuable checkpoint for anti-viral STING activation.
    DOI:  https://doi.org/10.1038/s42003-025-09380-2
  40. Kaohsiung J Med Sci. 2025 Dec 13. e70145
    Lysosome Evanescence Mediates Autophagic Flux Impairment in Glucose Imbalanced Environments.
    Yuan-Chen Cheng, Ling-Li Chang, Hung-Chen Wang, Wei-Chun Hung, Chia-Hua Hsieh, Yi-Hsuan Wang, Kuang-I Cheng.
      Schwann cells (SCs) support axonal function and promote nerve regeneration. This study investigated how various glucose concentrations influence SC viability, oxidative stress, and autophagy, which contribute to diabetic neuropathy. RSC96 SCs were cultured under five glucose conditions (0, 2.5, 5.5, 50, or 100 mM) for 24, 48, and 72 h. Cell viability was assessed by MTT; ROS levels were determined by DCFDA staining, and apoptosis and ER stress markers, as well as autophagy-related proteins were assessed by Western blotting. Autophagic flux was also analyzed using bafilomycin A1 and Cyto-ID. The results revealed time-dependent increases in cell death across all glucose conditions, especially under deprivation and low glucose (LG) conditions. ROS, CHOP, Bax, and cleaved caspase-3 levels increased from 24 to 72 h. The initial increase in the LC3B-II/I ratio indicated that autophagy was overactivated under glucose deprivation or LG conditions but impaired by 72 h, as indicated by reduced Lamp-2 expression. High glucose conditions led to early and persistent autophagy suppression, with minimal autophagic flux and vacuole formation. These findings demonstrate that SCs are sensitive to glucose levels and undergo distinct autophagic impairments through different mechanisms under persistent low or high glucose environments.
    Keywords:  LC3 puncta; Lamp‐2; Schwann cell; autophagy; glucose variability
    DOI:  https://doi.org/10.1002/kjm2.70145
  41. J Biol Chem. 2025 Dec 12. pii: S0021-9258(25)02902-3. [Epub ahead of print] 111050
    Enhanced Lysosomal Activity Prevents Infection with PrPSc and the Seeding Activity of α-Synuclein & Tau Prions.
    Robert C C Mercer, Nhat T T Le, Nadia A Mirza-Romero, Isabel C Orbe, Erin Flaherty, Joseph P DeFranco, Giada Lavigna, Jean R P Gatdula, Douglas G Fraser, Aravind Sundaravadivelu, Janelle S Vultaggio, Aaron B Beeler, Roberto Chiesa, Glenn C Telling, David A Harris.
      Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrPSc. The lysosome is the likely site of elacridar's anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for treatment of protein misfolding neurodegenerative diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2025.111050
  42. Aging Dis. 2025 Dec 05.
    Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases.
    Fabienne C Fiesel, Jens O Watzlawik, Michael G Heckman, Sophia G Blumenfeld, Michael J Rigby, Mohammed Kehili, Katja Lohmann, Christine Klein, Derek P Narendra, Clemens R Scherzer, Nilufer Ertekin-Taner, Neill R Graff-Radford, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer.
      Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.
    DOI:  https://doi.org/10.14336/AD.2025.1220
  43. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
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