bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–08–03
47 papers selected by
Viktor Korolchuk, Newcastle University
  1. Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
  2. The role of autophagy in the pathogenesis and treatment of multiple sclerosis.
  3. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  4. Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.
  5. ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains.
  6. Autophagy: Shedding Light on the Mechanisms and Multifaceted Roles in Cancers.
  7. Elevation of master autophagy regulator Tfeb in osteoblast lineage cells increases bone mass and strength.
  8. Targeted Degradation Technologies Utilizing Autophagy.
  9. Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
  10. Rab14 promotes Parkin mediated mitophagy.
  11. Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
  12. RNF13 mediates pH- and Ca2+-dependent regulation of lysosomal positioning.
  13. Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
  14. Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy.
  15. Different roles of ACSL3 and ACSL4 in autophagosome formation.
  16. Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
  17. Streptooctatin A induces autophagy and promotes α-synuclein clearance by directly binding to SUMO2 and inhibiting SUMOylation.
  18. Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
  19. NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies.
  20. Histone deacetylase 6 deacetylates and ubiquitinates ATG3 to regulate autophagy.
  21. FGF Signaling Promotes Lysosome Biogenesis in Chondrocytes via the Mannose Phosphate Receptor Pathway.
  22. The Parkinson Disease-Associated Mutant DNAJC13(N855S) Leads to Its Accelerated Degradation and Negatively Affects Macroautophagy and Retromer Complex-Mediated Dynamics.
  23. Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated osteoarthritis.
  24. Capsaicin Alleviates Autophagy-Lysosomal Dysfunction via PPARA-Mediated V-ATPase Subunit ATP6V0E1 Signaling in 3xTg-AD Mice.
  25. METTL3 Modulates Autophagy by Targeting TFEB in Myocardial Hypertrophy.
  26. Post-translational modifications orchestrate mTOR-driven cell death in cardiovascular disease.
  27. Role of Prohibitins as Guardians of mitochondrial homeostasis.
  28. Cathartocytosis: Jettisoning of cellular material during reprogramming of differentiated cells.
  29. The p97 ATPase and its adaptor UBXD8 maintain peroxisome pools by preventing pexophagy.
  30. Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.
  31. Delayed administration of rapamycin inhibits glial scar formation through upregulating matrilin-3 in an autophagy-dependent manner in ischemic stroke.
  32. A structural switch reveals how to disarm USP30 and unlock mitophagy.
  33. Targeting WSTF degradation to resolve chronic inflammation.
  34. CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
  35. TORC2 and MAPK signaling pathways regulate mitochondrial degradation induced by iron starvation in Schizosaccharomyces pombe.
  36. A simple, accurate method for the measurement of lysosomal activity.
  37. A newly revealed signaling pathway may explain the conundrum of how FGF21 simultaneously increases insulin sensitivity and autophagy.
  38. Nanotechnology-targeted modulation of mitophagy in cancer therapy: Progress and challenges.
  39. CORM-3 mitigates osteoarthritis by anti-inflammation and enhancing autophagy via inhibiting MAPK and mTOR pathways.
  40. Membrane Contact Sites in Proteostasis and ER Stress Response.
  41. Modern methods of detecting mitophagy.
  42. Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.
  43. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  44. Phosphoinositides as regulators of membrane contact sites.
  45. Mitophagy's impacts on cancer and neurodegenerative diseases: implications for future therapies.
  46. Lessons in longevity from blood stem cells under protein stress.
  47. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  1. Nat Cell Biol. 2025 Jul 25.
    Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
    Elias Adriaenssens, Stefan Schaar, Annan S I Cook, Jan F M Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H Hurley, Sascha Martens.
      Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01712-y
  2. Autophagy Rep. 2025 ;4(1): 2529196
    The role of autophagy in the pathogenesis and treatment of multiple sclerosis.
    Giulio Righes, Luana Semenzato, Konstantinos Koutsikos, Veronica Zanato, Paolo Pinton, Carlotta Giorgi, Simone Patergnani.
      Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.
    Keywords:  Multiple sclerosis; autophagy; ferritinophagy; lipophagy; mielinophagy; mitophagy; therapy
    DOI:  https://doi.org/10.1080/27694127.2025.2529196
  3. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  4. Nat Struct Mol Biol. 2025 Jul 25.
    Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.
    Rachel M Jansen, Clément Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James H Hurley.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface on CASTOR1 that is distal to the arginine pocket. The structure shows how arginine-triggered loop ordering in CASTOR1 blocks the MIOS-binding interface, switches off its binding to GATOR2 and, thus, communicates to downstream mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41594-025-01635-0
  5. EMBO J. 2025 Jul 29.
    ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains.
    Maike Reinders, Bojana Kravic, Pinki Gahlot, Sandra Koska, Johannes van den Boom, Nina Schulze, Sophie Levantovsky, Stefan Kleine, Markus Kaiser, Yogesh Kulathu, Christian Behrends, Hemmo Meyer.
      The cellular response to lysosomal damage involves fine-tuned mechanisms of membrane repair, lysosome regeneration and lysophagy, but how these different processes are coordinated is unclear. Here we show in human cells that the deubiquitinating enzyme ATXN3 helps restore integrity of the lysosomal system after damage by targeting K48-K63-branched ubiquitin chains on regenerating lysosomes. We find that ATXN3 is required for lysophagic flux after lysosomal damage but is not involved in the initial phagophore formation on terminally damaged lysosomes. Instead, ATXN3 is recruited to a distinct subset of lysosomes that are decorated with phosphatidylinositol-(4,5)-bisphosphate and that are not yet fully reacidified. There, ATXN3, along with its partner VCP/p97, targets and turns over K48-K63-branched ubiquitin conjugates. ATXN3 thus facilitates degradation of a fraction of LAMP2 via microautophagy to regenerate the lysosomal membrane and to thereby reestablish degradative capacity needed also for completion of lysophagy. Our findings identify a key role of ATXN3 in restoring lysosomal function after lysosomal membrane damage and uncover K48-K63-branched ubiquitin chain-regulated regeneration as a critical element of the lysosomal damage stress response.
    Keywords:  Autophagy; Lysosome; Membrane; Stress Response; Ubiquitin
    DOI:  https://doi.org/10.1038/s44318-025-00517-x
  6. Biomolecules. 2025 Jun 22. pii: 915. [Epub ahead of print]15(7):
    Autophagy: Shedding Light on the Mechanisms and Multifaceted Roles in Cancers.
    Hongmei You, Ling Wang, Hongwu Meng, Jun Li, Guoying Fang.
      Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy.
    Keywords:  ATG 2; autophagy 1; cancers 3; cell death 4
    DOI:  https://doi.org/10.3390/biom15070915
  7. JCI Insight. 2025 Jul 29. pii: e191688. [Epub ahead of print]
    Elevation of master autophagy regulator Tfeb in osteoblast lineage cells increases bone mass and strength.
    Alicen James, James A Hendrixson, Ilham Kadhim, Adriana Marques-Carvalho, Jacob Laster, Julie Crawford, Jeff Thostenson, Visanu Wanchai, Amy Y Sato, Intawat Nookaew, Jinhu Xiong, Maria Almeida, Melda Onal.
      Autophagy is a recycling pathway in which damaged proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Autophagy insufficiency is thought to contribute to osteoporosis. Accordingly, autophagy elimination from the osteoblast lineage reduces bone formation and bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of endogenous transcription factor EB gene (Tfeb) in osteoblast lineage cells in vivo via CRISPR activation (TfebCRa mice). Elevated Tfeb stimulated autophagy and lysosomal biogenesis in osteoblasts. TfebCRa mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Increases in cortical thickness was due to increased periosteal bone formation. Tfeb elevation also increased femoral trabecular bone volume. These changes increased bone strength of TfebCRa mice. Female TfebCRa mice displayed a progressive increase in bone mass and at 12 months of age had high cortical thickness and trabecular bone volume. Increased vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed that Tfeb elevation increased proliferation and mineral deposition. Overall, these results demonstrate TFEB-driven stimulation of autophagy in osteoblast lineage cells is associated with increased bone formation and strength and may represent an effective approach to combat osteoporosis.
    Keywords:  Autophagy; Bone biology; Cell biology; Osteoclast/osteoblast biology; Osteoporosis
    DOI:  https://doi.org/10.1172/jci.insight.191688
  8. Int J Mol Sci. 2025 Jul 08. pii: 6576. [Epub ahead of print]26(14):
    Targeted Degradation Technologies Utilizing Autophagy.
    Zeyu Zhou, Jiaming Liang, Binghua Cheng, Yanyan Li, Wenjie Zhou, Hui Tian, Wenli Shi, Ke Liu, Lijing Fang, Hongchang Li, Ximing Shao.
      Targeted degradation technologies, primarily referring to targeted protein degradation, have emerged as promising drug discovery strategies. In contrast to traditional "occupancy-driven" inhibition approaches, these technologies ingeniously leverage the cell's endogenous degradation mechanisms to achieve specific elimination of disease-causing targets. Autophagy, a highly conserved cellular clearance pathway, possesses broad substrate recognition capabilities, enabling degradation of not only individual proteins but also protein aggregates, damaged organelles, and invading pathogens. Given these characteristics, researchers are actively exploring the application of autophagy mechanisms in targeted degradation technologies. Herein, we summarize recent advances in autophagy-dependent degradation approaches, including autophagosome tethering compounds (ATTEC), autophagy-targeting chimeras (AUTAC), autophagy-targeting Chimera (AUTOTAC), chaperone-mediated autophagy (CMA)-based methods, nanotechnology-based strategies, and the newly introduced autophagy-induced antibody (AUTAB) technique, highlighting their mechanisms, advantages, and potential applications in treating tumors, neurodegenerative diseases, and other challenging conditions.
    Keywords:  autophagy; drug discovery; lysosome; targeted protein degradation
    DOI:  https://doi.org/10.3390/ijms26146576
  9. J Cell Biochem. 2025 Jul;126(7): e70056
    Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
    Min Tang, Ikram Outissint, Yijing Chen, Xun Gong.
      Mitophagy, a selective autophagic process, is critical for maintaining mitochondrial quality and cellular homeostasis. It plays a dual role, facilitating cell survival by removing damaged mitochondria or contributing to programmed cell death in certain conditions. Dysregulation of mitophagy is implicated in various diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancers. This review examines the key regulatory mechanisms of mitophagy, focusing on pathways such as the PINK1-Parkin, BNIP3/NIX, and FUNDC1 pathways, alongside emerging modulators. Notably, mitophagy is frequently associated with various cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis. Primarily, mitophagy functions as a protective mechanism rather than a direct trigger of cell death. It may be connected to cell death when its capacity is overwhelmed rather than actively promoting the process. For instance, impaired mitophagy exacerbates neurodegeneration in Parkinson's and Alzheimer's diseases, while its activation protects against ischemic injury in cardiovascular diseases. In cancer, mitophagy is paradoxical, as it either inhibits tumor growth or promotes survival under stress. Therapeutic interventions targeting mitophagy, including small-molecule modulators, show promise in preclinical studies; however, they require further clinical validation. Advancements in imaging techniques, single-cell omics, and high-throughput screenings are anticipated to deepen our understanding of mitophagy dynamics and therapeutic potential. This review highlights mitophagy as a pivotal target for treating diseases associated with mitochondrial dysfunction, providing insights into innovative therapeutic strategies.
    Keywords:  cell death pathways; metabolic syndromes; mitophagy; neurodegenerative disorders; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70056
  10. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  11. Life Sci. 2025 Jul 30. pii: S0024-3205(25)00525-9. [Epub ahead of print] 123890
    Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
    Sarmistha Sarkar, Aindrila Chattopadhyay, Debasish Bandyopadhyay.
      High mortality rates due to cardiovascular diseases (CVDs) fascinate the scientists worldwide in the past few decades to discover potent therapeutic strategies to save the victims. The myocardium being a highly active tissue, mitochondrial homeostasis and mitochondrial quality control system are crucial for maintaining optimal cardiac performance. Mitochondrial quality control mechanism is a finely tuned regulatory network encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy and is an integral component of the mitochondrial response to stressor stimuli. Mitochondrial dynamics including the fusion and fission of mitochondrial membranes is regulated by an extensively conserved mechanism comprising a group of mitochondrial membrane proteins belonging to the dynamin family of GTPases. Emerging evidences indicate that defects in mitochondrial fusion or fission are intrinsically correlated with the pathophysiology of CVDs. Mitophagy is a kind of selective autophagy which removes damaged or redundant mitochondria. Experimental findings demonstrated that impairment of mitophagy in cardiomyocytes induces the accumulation of dysfunctional mitochondria, leading to the disruption of cellular homeostasis and consequently precipitating various CVDs. These findings speculate that pharmacological modulation of mitochondrial homeostasis including mitochondrial dynamics and mitophagy may represent a potential therapeutic approach in restoring cardiac physiology. This review summarizes the prevailing insight into the impact of disturbed mitochondrial dynamics and mitophagy in the pathogenesis of CVDs and also delineates the therapeutic potential of several relevant regulatory drugs that target mitochondrial function and quality control in alleviating mitochondrial impairment-related cardiac dysfunction.
    Keywords:  Cardiomyocytes; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.lfs.2025.123890
  12. Cell Rep. 2025 Jul 24. pii: S2211-1247(25)00824-1. [Epub ahead of print]44(8): 116053
    RNF13 mediates pH- and Ca2+-dependent regulation of lysosomal positioning.
    Lan Thi Trinh, Anh Van Vu, Seunghye Shin, Chanhaeng Lee, Sang-Hee Park, Eun-Bee Cho, Yunseok Heo, Hyun Jin Kim, Sungjoo Kim, Jong-Bok Yoon.
      Environmental factors such as extracellular pH (pHe) and nutrition status affect lysosomal localization and autophagy, but how pHe, intracellular pH (pHi), and Ca2+ regulate lysosome transport is not well understood. Here, we identify RNF13 as a key regulator of lysosomal positioning via pHi- and Ca2+-dependent degradation of ARL8B. Ca2+-activated apoptosis-linked gene 2 (ALG-2) promotes retrograde lysosomal transport while increasing pHi and decreasing lysosomal pH (pHlys). Elevated pHi deprotonates RNF13 at His332, enabling its interaction with Ca2+-bound ALG-2 and inhibition of ARL8B-mediated anterograde transport. Alkaline pHe elevates pHlys and activates the lysosomal Ca2+ channel TRPML3, enhancing RNF13 activity and driving lysosomes toward a perinuclear position. Thus, starvation or alkaline pHe induces ALG-2 activation and pHi elevation, facilitating RNF13-mediated ARL8B degradation. In contrast, acidic pHi suppresses RNF13, keeping ARL8B levels high even when ALG-2 is active. These findings reveal a coordinated mechanism involving Ca2+ signaling and pH dynamics in regulating lysosomal positioning.
    Keywords:  ARL8B; CP: Cell biology; RNF13; TRPML1; TRPML3; autophagy; intracellular Ca(2+); intracellular pH; lysosomal positioning; lysosome; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116053
  13. Brain. 2025 Jul 29. pii: awaf278. [Epub ahead of print]
    Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
    Kengo Kora, Takeshi Yoshida, Atsushi Yokoyama, Kei Fujiwara, Naoko Yano, Taisei Kayaki, Satoshi Kajimoto, Kinuko Nishikawa, Hidetoshi Sakurai, Junko Takita.
      X-linked myotubular myopathy is a severe congenital muscle disorder caused by pathogenic variants in the MTM1 gene, which encodes the phosphoinositide phosphatase myotubularin. Muscle biopsies from patients with X-linked myotubular myopathy exhibit distinctive histopathological features, including small, rounded myofibres with centrally located nuclei, indicating a developmental defect in muscle maturation. While earlier studies have indicated that myotubularin dysfunction causes dysregulation of mechanistic target of rapamycin complex 1 (mTORC1) signalling, the underlying mechanisms and phenotypic impact on human muscle cells remain poorly understood. Currently, there are no approved therapies available for the treatment of this disorder. In this study, we established an induced pluripotent stem cell-based model of X-linked myotubular myopathy using two pairs of isogenic induced pluripotent stem cells: healthy-control versus MTM1-knockout and patient-derived versus gene-corrected induced pluripotent stem cells. Through MyoD-inducible myogenic differentiation, this model successfully recapitulates the key pathological features of X-linked myotubular myopathy, including elevated phosphatidylinositol-3-phosphate levels, hyperactivation of mTORC1 signalling, and increased expression of integrin-β1 and dynamin 2. We identified impaired lysosomal dynamics as a novel pathogenic mechanism in X-linked myotubular myopathy. Our induced pluripotent stem cell-derived X-linked myotubular myopathy myotubes exhibited an abnormal redistribution of lysosomes, with peripheral accumulation, leading to abnormally activated mTORC1 signalling. FYCO1 knockdown, a key regulator of lysosomal trafficking, ameliorated this hyperactivation of mTORC1 signalling. Comprehensive transcriptome analysis revealed distinct gene expression patterns associated with altered mTORC1 signalling and lysosomal localisation in X-linked myotubular myopathy myotubes. Network analysis suggested the central role of the mTORC1 signalling pathway and its connections to disrupted muscle development and differentiation. To investigate the influence of mTORC1 signalling and myotubularin deficiency on myogenic differentiation, we established two mouse myoblast models: one with constitutively activated mTORC1 signalling and another with Mtm1 knockout. Increased mTORC1 signalling in mouse myoblasts impaired myogenic differentiation, and this impairment was reversed by mTORC1 inhibitor rapamycin. Notably, rapamycin treatment also ameliorated the impaired myogenic differentiation observed in Mtm1-knockout mouse myoblasts, supporting the causative role of mTORC1 hyperactivation in X-linked myotubular myopathy pathogenesis. In conclusion, our findings establish the first human cell model of XLMTM, revealing that myotubularin deficiency leads to impaired lysosomal dynamics, which in turn causes mTORC1 dysregulation, a critical factor in the early stage of myogenic differentiation in X-linked myotubular myopathy. These findings provide new insights into the pathogenesis of X-linked myotubular myopathy and suggest that targeting mTORC1 signalling may be a promising therapeutic strategy for this debilitating disorder.
    Keywords:  MTM1; X-linked myotubular myopathy; induced pluripotent stem cell; lysosomal dynamics; mTORC1 signalling; myogenic differentiation
    DOI:  https://doi.org/10.1093/brain/awaf278
  14. Aging (Albany NY). 2025 Jul 28. 17
    Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy.
    Andrei O Zheltukhin, Peter M Chumakov, Andrei V Budanov.
      Sestrins, evolutionarily conserved stress-responsive proteins, are increasingly recognized for their potential role in lifespan regulation. This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric deprivation (CD) in the model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CD, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1's interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.
    Keywords:  aging; autophagy; mTOR; sesn-1
    DOI:  https://doi.org/10.18632/aging.206290
  15. J Cell Sci. 2025 Jul 15. pii: jcs263677. [Epub ahead of print]138(14):
    Different roles of ACSL3 and ACSL4 in autophagosome formation.
    Shun Kato, Naoki Okada, Toshiki Ohata, Takefumi Uemura, Satoshi Waguri, Yuichi Wakana, Hiroki Inoue, Kohei Arasaki, Mitsuo Tagaya.
      Acyl-CoA synthetases (ACSLs) are a family of enzymes that convert intracellular fatty acids into acyl-CoA. A previous study has demonstrated that the yeast ACSL Faa1 (a homolog of mammalian ACSL4) is involved in autophagosome membrane elongation. In the present study, we investigated the involvement of ACSL3, a key enzyme responsible for lipid droplet formation, in autophagosome formation and compared its role with that of ACSL4. Knockdown of ACSL3 impaired starvation-induced autophagy concomitant with the formation of enlarged autophagosome-like structures negative for WIPI2, whereas its overexpression resulted in the formation of WIPI2-positive, but LC3-negative dots, under normal nutrition conditions, likely in an enzymatic activity-independent manner. In contrast, ACSL4 knockdown inhibited starvation-induced autophagosome formation, whereas its overexpression caused autophagosome formation under normal nutrition conditions. Inhibition of autophagosome formation in ACSL4-depleted cells could be rescued by ethanolamine, suggesting a deficit of phosphatidylethanolamine in ACSL4-depleted cells. These results suggest that ACSL3 and ACSL4 are involved in different stages of autophagosome formation - ACSL3 in the formation of fusion-competent autophagosomal membranes and ACSL4 in the formation of autophagosomes.
    Keywords:  ACSL3; ACSL4; Autophagy; Lipid droplet; Lipid metabolism
    DOI:  https://doi.org/10.1242/jcs.263677
  16. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00859-9. [Epub ahead of print]44(8): 116088
    Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
    Ming-Yuan Su, Fei Teng, Shan Wang, Xinyi Mai, Huan Zeng, Juan Li, Xiaoxiao Song, Xi Wang, Goran Stjepanovic.
      Mammalian cells regulate growth by integrating environmental cues through the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The human GATOR2 complex, comprising WDR59, WDR24, Mios, Sec13, and Seh1l, is key to mTORC1 regulation. Under amino acid deprivation, GATOR2 is inhibited through interactions with cytosolic leucine sensor Sestrin2 and arginine sensor cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Amino acid abundance relieves this inhibition, allowing GATOR2 to antagonize the repressor GATOR1. Despite its importance, GATOR2's inhibition mechanisms were unclear. Here, we present cryo-electron microscopy (cryo-EM) structures of GATOR2 in three inhibitory states: CASTOR1 bound, Sestrin2 bound, and dual bound. CASTOR1 engages the Mios WD40 β-propellers, while Sestrin2 interacts with the WDR24-Seh1l subcomplex, inducing conformational movements. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) reveals dynamic motions in apo-GATOR2 and its complexes with amino acid sensors, as well as the effects of amino acid supplementation. These findings unravel the interactions between GATOR2 and amino acid sensors, providing a perspective on the regulation of the mTORC1 pathway by nutrient-sensing machinery.
    Keywords:  CASTOR1; CP: Metabolism; CP: Molecular biology; GATOR1; GATOR2; HDX-MS; Sestrin2; amino acid sensing; cryo-EM; mTOR complex 1
    DOI:  https://doi.org/10.1016/j.celrep.2025.116088
  17. Biochem Pharmacol. 2025 Jul 26. pii: S0006-2952(25)00460-5. [Epub ahead of print] 117195
    Streptooctatin A induces autophagy and promotes α-synuclein clearance by directly binding to SUMO2 and inhibiting SUMOylation.
    Jongtae Roh, Jun-Pil Jang, Gun-Hee Kim, Mina Jang, Jihun Park, Taehoon Oh, Yong-Jun Kwon, Jong Seog Ahn, Jae-Hyuk Jang, Sung-Kyun Ko.
      Autophagy is a self-degradative process that is essential for cellular homeostasis and survival. Discovery of autophagy-modulatory compounds and the subsequent investigation of their mode of action can provide essential information to understand the factors associated with autophagy and autophagy-related diseases. In this study, we reported a novel autophagy regulator, Streptooctatin A (STR A), which sequentially induces autophagy. Using thermal shift assay, we identified human SUMO2 as a binding candidate of STR A. This interaction was further validated by SPR analysis, with a 16.0 μM of dissociation constant. Additionally, STR A induces autophagy by inhibiting SUMOylation process. Mechanistically, we suggest that STR A-mediated SUMO2 inhibition affects autophagy process through enhancing nuclear translocation of FoxO3a by approximately 1.9-fold, and upregulating autophagy-related genes such as ULK1 and Atg family genes, by 2.19- to 5.26-fold. In cellular Parkinson's disease models, autophagy induction by STR A-mediated deSUMOylation effectively promoted clearance of α-synuclein aggreagates by up to 95 % at 20 μM concentration. Consequently, our findings suggest that STR A is a promising chemical probe for studying SUMO2 function and may serve as a potential therapeutic leads for reducing α-synuclein aggregates in neurodegenerative diseases, especially Parkinson's disease.
    Keywords:  Autophagy; Parkinson’s disease; Protein-protein interaction; SUMO2; Streptooctatin A; α-synuclein
    DOI:  https://doi.org/10.1016/j.bcp.2025.117195
  18. Neurochem Res. 2025 Jul 28. 50(4): 251
    Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
    Qian Yu, Li Li, Shuyi Yu, Jialin Han, Qian Cheng, Zhikang Cui, Hang Chen, Ming Li, Zhiming Lu.
      Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.
    Keywords:  Alzheimer’s disease; Aβ; Mitochondrial dysfunction; Mitophagy; p-tau
    DOI:  https://doi.org/10.1007/s11064-025-04490-z
  19. Exp Mol Pathol. 2025 Jul 24. pii: S0014-4800(25)00038-3. [Epub ahead of print]143 104988
    NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies.
    Ifat Alsharif.
      Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau (p-tau) and the formation of neurofibrillary tangles. Autophagy, a fundamental cellular degradation pathway, plays a pivotal role in maintaining proteostasis by facilitating the clearance of misfolded and aggregated proteins. In tauopathies, however, autophagic processes are often impaired, contributing to the pathological buildup of p-tau. NVP-BEZ235, a dual inhibitor of the mammalian target of rapamycin (mTOR) and PI3K, has previously been evaluated in phase I clinical trials for solid tumors and lymphomas. In this study, we investigated the therapeutic potential of NVP-BEZ235 in tauopathy models, both in vitro and in vivo. In SH-SY5Y cells stably expressing human P301L-mutant tau (SH-Tau), NVP-BEZ235 treatment induced a time-dependent increase in LC3B-II and a decrease in p62 levels, consistent with enhanced autophagic activity. Autophagic flux analysis further confirmed the promotion of autophagy upon mTOR pathway inhibition. NVP-BEZ235 significantly reduced tau phosphorylation at multiple residues, including Ser262, Ser396, Ser404, and Thr231, without eliciting cytotoxic effects. In a transgenic mouse model of tauopathy (P301S), chronic treatment with NVP-BEZ235 (20 mg/kg/day for two months) resulted in a marked reduction of both RIPA-soluble and -insoluble p-tau species in the brain. Spatial learning and memory, assessed through Morris water maze and novel object recognition tests, were significantly improved in treated mice. Furthermore, NVP-BEZ235 administration reduced neuroinflammatory markers and pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6), while also enhancing autophagic markers in brain tissue. Hematological analysis and organ histology revealed no signs of systemic toxicity. Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.
    Keywords:  Autophagy; NVP-BEZ235; P-tau accumulation; Tauopathies; mTOR inhibition
    DOI:  https://doi.org/10.1016/j.yexmp.2025.104988
  20. Cell Death Differ. 2025 Jul 30.
    Histone deacetylase 6 deacetylates and ubiquitinates ATG3 to regulate autophagy.
    Jiayu Yao, Ziyang Zhao, Yousheng Chen, Xuan Xu, Ying Yang, Weiying Yue, Xingjuan Shi.
      ATG3 (autophagy-related gene 3), an E2 like enzyme, plays a vital role in autophagy by regulating the lipidation modification of LC3 (microtubule-associated protein 1A/1B-light chain 3). Although the level of ATG3 can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Histone deacetylase 6 (HDAC6) is involved in multiple cellular activities by regulating acetylation of its substrates such as α-tubulin and cortactin. Here, we revealed a novel function of HDAC6 in autophagy regulation by mediating the post-translational modifications of ATG3. We found that HDAC6 interacts with ATG3 and deacetylates ATG3. In addition, HDAC6 acts its ubiquitin E3 ligase activity and ubiquitinates ATG3 at lysine 272, leading to ATG3 degradation. Intriguingly, lysine 272 of ATG3 is targeted for deacetylation as well as ubiquitination by HDAC6. Further study showed that HDAC6 participates in autophagy by mediating ATG3 degradation. Taken together, our findings uncover a novel role of HDAC6 in autophagy regulation by mediating the protein modification and degradation of ATG3.
    DOI:  https://doi.org/10.1038/s41418-025-01553-0
  21. Traffic. 2025 Jul-Sep;26(7-9):26(7-9): e70013
    FGF Signaling Promotes Lysosome Biogenesis in Chondrocytes via the Mannose Phosphate Receptor Pathway.
    Laura Cinque, Maria Iavazzo, Gennaro Di Bonito, Elena Polishchuk, Rossella De Cegli, Carmine Settembre.
      The mannose 6-phosphate (M6P) pathway is critical for lysosome biogenesis, facilitating the trafficking of hydrolases to lysosomes to ensure cellular degradative capacity. Fibroblast Growth Factor (FGF) signaling, a key regulator of skeletogenesis, has been linked to the autophagy-lysosomal pathway in chondrocytes, but its role in lysosome biogenesis remains poorly characterized. Here, using mass spectrometry, lysosome immune-purification, and functional assays, we reveal that RCS (Swarm rat chondrosarcoma cells) lacking FGF receptors 3 and 4 exhibit dysregulations of the M6P pathway, resulting in hypersecretion of lysosomal enzymes and impaired lysosomal function. We found that FGF receptors control the expression of M6P receptor genes in response to FGF stimulation and during cell cycle via the activation of the transcription factors TFEB and TFE3. Notably, restoring M6P pathway-either through gene expression or activation of TFEB-significantly rescues lysosomal defects in FGFR3;4-deficient RCS. These findings uncover a novel mechanism by which FGF signaling regulates lysosomal function, offering insights into the control of chondrocyte catabolism and the understanding of FGF-related human diseases.
    Keywords:  FGF signaling; MPR trafficking pathway; TFEB; chondrocytes; lysosome; mannose phosphate receptors
    DOI:  https://doi.org/10.1111/tra.70013
  22. J Cell Physiol. 2025 Jul;240(7): e70074
    The Parkinson Disease-Associated Mutant DNAJC13(N855S) Leads to Its Accelerated Degradation and Negatively Affects Macroautophagy and Retromer Complex-Mediated Dynamics.
    Anna Stein, Stella Vo, Christian Freese, Joram Kluge, Joanna Maus, Ingrid Koziollek-Drechsler, Beate Silva, Christian Behl, Albrecht M Clement.
      While Parkinson's disease has a multifactorial etiology, 5%-10% of cases present with identifiable disease-causing gene mutations. Further investigation into these mutations is a way to identify underlying pathologic mechanism. One of the rare Parkinson-associated genes is DNAJC13, coding for an endosome-associated protein. Several lines of evidence suggest that disturbed endosomal pathways are instrumental in the development of Parkinson pathology. Recently, we have shown that DNAJC13/RME-8 is a positive modulator of autophagy, a lysosome-associated degradative process. Here, we further characterize the role of the disease-linked DNAJC13(N855S) mutant and perform biochemical, cell biological, co-localization, and expression analysis by employing a newly established cell line with reduced DNAJC13 expression and by transiently expressing the DNAJC13(N855S) mutant variant. We observed that the DNAJC13(N855S) variant is less stable than the wild-type protein and might thus impact proteostasis. Furthermore, the protein has functional deficits as it cannot compensate for the impaired autophagic activity in cells with chronically reduced DNAJC13 levels. In addition, the DNAJC13(N855S) showed a dominant negative effect on the distribution of the cation-independent mannose-6-phosphate receptor without affecting overall cathepsin D levels or activity. Lastly, we observed a decreased expression of several genes related to autophagy induction and biogenesis in stable DNAJC13 knockdown cells. Our data point toward a loss-of-function mechanism of the DNAJC13(N855S) variant and that chronically reduced DNAJC13 protein levels result in a reduced expression of genes largely involved in endosomal traffic and autophagosome biogenesis. The DNAJC13(N855S) mutant might thus cause disease in part by its instability and in part by a dominant negative effect on the autophagic pathway. These data support a pivotal role of endosomal pathway impairment in Parkinson's disease pathogenesis.
    Keywords:  DNAJC13; autophagy; endosomal traffic; endosome
    DOI:  https://doi.org/10.1002/jcp.70074
  23. Autophagy. 2025 Jul 29.
    Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated osteoarthritis.
    Xiaomin Kang, Wenjuan Liu, Xiao Ma, Dongxu Feng, Hongzhi Sun, Shufang Wu.
      Obesity, a major risk factor for osteoarthritis (OA), is related to increased circulating levels of free fatty acids (FFAs). However, the molecular mechanism underlying this metabolic OA phenotype remains unknown. We found that mice fed a high-fat diet (HFD) became obese and developed OA in their knee joints. Macroautophagy/autophagy activity was significantly reduced in articular cartilage of mice fed an HFD or in chondrocytes exposed to FFAs. Using conditional knockout (cKO) mice with cartilage-specific deletion of Atg7 to inhibit autophagy in vivo and shAtg7-lentiviral-transduced chondrocytes in vitro, we showed that autophagy deficiency aggravated HFD-induced OA progression and chondrocyte extracellular matrix (ECM) degradation. Mechanistically, STING1 was degraded in an autophagy-dependent manner. Autophagy deficiency increased STING1 levels, in turn activating the STING1-TBK1-IRF3 and MAP2K3/MKK3-MAPK/p38 signaling pathways, thereby triggering cartilage ECM degradation. These findings suggested that the HFD-autophagy-STING1 axis played a pivotal role in OA development, providing a potential therapeutic strategy for obesity-associated OA.
    Keywords:  ATG7; STING1; autophagy; high-fat diet; obesity; osteoarthritis
    DOI:  https://doi.org/10.1080/15548627.2025.2541388
  24. Adv Sci (Weinh). 2025 Jul 28. e02707
    Capsaicin Alleviates Autophagy-Lysosomal Dysfunction via PPARA-Mediated V-ATPase Subunit ATP6V0E1 Signaling in 3xTg-AD Mice.
    Haitao Yu, Jia Chen, Fangzhou Wang, Dongdong Jia, Shuguang Bi, Yuming Mao, Yu-Qi Zhang, Tian-Long Gao, Liu Yang, Jia-Xu Du, Zi-Han Zhou, Xi-Chen Zhu, Gao-Shang Chai.
      Autophagy-lysosomal pathway deficits contribute to the accumulation of amyloid-β (Aβ), Tau, and lipid droplets in Alzheimer's disease (AD). Capsaicin, a specific agonist of transient receptor potential vanilloid 1 (TRPV1), can improve cognitive function in AD patients, but the detailed mechanism is still unclear. Here, it is revealed that capsaicin ameliorated AD-related pathology by activating peroxisome proliferator-activated receptor alpha (PPARA/PPARα, a key regulator of lipid metabolism) to promote lipid metabolism and reverse autophagy-lysosomal deficits. Molecular mechanism research found that capsaicin significantly activated the PPAR signaling pathway to promote lipid metabolism, with PPARA identified as the key transcription factor. In addition, capsaicin upregulated ATP6V0E1 (V-ATPase V0 complex subunit e1, involved in lysosomal acidification) expression through PPARA, restoring V-ATPase activity. This enhanced lysosomal acidification facilitated lipophagy (autophagic clearance of lipid droplets), while promoting the clearance of Aβ and Tau aggregates via the autophagy-lysosomal pathway. Further, inhibition of ATP6V0E1 and PPARA expression blocked the effect of capsaicin on alleviating AD lipid pathology and cognitive deficits through autophagy-lysosomal flux. Taken together, capsaicin promotes lipid metabolism, reduces lipid deposition, and attenuates AD-related pathologies, while PPARA-ATP6V0E1-V-ATPase signaling mediated autophagy-lysosomal pathway plays a key role in this process.
    Keywords:  ATP6V0E1; Alzheimer's disease; PPARA; V‐ATPase; autophagy; capsaicin
    DOI:  https://doi.org/10.1002/advs.202502707
  25. Int Heart J. 2025 ;66(4): 615-627
    METTL3 Modulates Autophagy by Targeting TFEB in Myocardial Hypertrophy.
    Yanan Xie, Wei Jiao, Hongchao Wang, Shaowei Kang, Jie Hao, Jinming Liu, Yongjun Li, Bingyan Guo.
      The aim of this study was to investigate the mechanism of m6A methylation in pathological myocardial hypertrophy (PMH), focusing on whether the methyltransferase METTL3 regulates the expression and nuclear translocation of the transcription factor EB (TFEB), thereby affecting autophagic activity and exacerbating the development of myocardial hypertrophy.An in vivo PMH model was established in mice via transverse aortic constriction (TAC), and an in vitro hypertrophy model was established using H9C2 cells stimulated with angiotensin II (AngII). HE staining, Western blotting, qRT-PCR, immunofluorescence, and dual-color autophagy flux analyses were employed to detect the expression of autophagy-related proteins (LC3, Beclin-1, P62, ATG5) and apoptosis levels. Changes in TFEB and key m6A-related enzymes (METTL3, ALKBH5, heterogeneous nuclear ribonucleoprotein D [HNRNPD]) were examined, and gene overexpression or knockdown experiments were performed to clarify their roles in regulating autophagy and myocardial hypertrophy. Finally, m6A MeRIP-qPCR and RIP-qPCR were conducted to explore the effect of METTL3 on m6A modification and the stability of TFEB transcripts, verifying the interplay between METTL3 and TFEB and its impact on autophagy.In both the in vivo and in vitro hypertrophy models, autophagy was significantly impaired and apoptosis was elevated, while TFEB mRNA and protein expression and its nuclear localization were clearly reduced. At the same time, global m6A methylation was markedly increased, accompanied by upregulation of METTL3 and HNRNPD, as well as downregulation of ALKBH5. Functional assays indicated that METTL3 overexpression further inhibited autophagy-related protein expression and autophagic flux, whereas METTL3 knockdown partially restored autophagy. Mechanistic studies revealed that METTL3 modulates TFEB pre-mRNA stability by influencing the binding efficiencies of ALKBH5 and HNRNPD, resulting in decreased TFEB expression. Conversely, overexpression of TFEB could partly counteract the autophagy impairment caused by METTL3 overexpression and reciprocally regulate the expression of METTL3, ALKBH5, and HNRNPD.METTL3 mediates the inhibition of TFEB via m6A modification, thereby impairing autophagy and aggravating myocardial hypertrophy. These findings suggest that the m6A-TFEB axis may serve as a novel therapeutic target for preventing and treating myocardial hypertrophy and heart failure, offering new insights into the intervention of cardiac remodeling-related diseases.
    Keywords:  Autophagic flux regulation; Cardiac remodeling; Epitranscriptomic regulation; Heart failure progression; m6A modification
    DOI:  https://doi.org/10.1536/ihj.24-683
  26. Front Cardiovasc Med. 2025 ;12 1620669
    Post-translational modifications orchestrate mTOR-driven cell death in cardiovascular disease.
    Jiawei Guo, Yiting Wu, Zhengdong Wan, Zhaoshan Zhang.
      The mechanistic target of rapamycin (mTOR) signaling pathway is a central regulator of cellular physiology, modulating processes such as metabolism, protein synthesis, growth, and various forms of cell death. Increasing evidence has revealed that dysregulation of mTOR activity, often triggered or exacerbated by aberrant post-translational modifications (PTMs), contributes to the onset and progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction, heart failure, and ischemia-reperfusion injury. PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation alter mTOR's upstream regulators and downstream effectors, influencing the balance between apoptosis, autophagy, pyroptosis, and ferroptosis. These regulatory mechanisms provide a molecular basis for cell fate decisions during cardiovascular stress and injury. In this review, we systematically summarize recent advances in the understanding of PTM-mediated control of mTOR signaling, with a focus on cardiovascular pathophysiology. We also highlight emerging therapeutic strategies that target PTMs or the mTOR axis, including mTOR inhibitors, AMPK activators, proteasome blockers, and SUMOylation modulators, all of which show promise in preclinical or clinical settings. Understanding how PTMs fine-tune mTOR activity and cell death may pave the way for novel, targeted interventions in cardiovascular medicine and offer potential avenues for the development of precision therapies.
    Keywords:  MTOR signaling; cardiovascular diseases; cell death; protein modifications; therapeutic strategies
    DOI:  https://doi.org/10.3389/fcvm.2025.1620669
  27. Mitochondrion. 2025 Jul 28. pii: S1567-7249(25)00072-8. [Epub ahead of print] 102075
    Role of Prohibitins as Guardians of mitochondrial homeostasis.
    Sabrina Champsi, David A Hood.
      Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.
    Keywords:  Aging; Apoptosis; Mitochondria; Mitophagy; Prohibitin
    DOI:  https://doi.org/10.1016/j.mito.2025.102075
  28. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00841-1. [Epub ahead of print]44(8): 116070
    Cathartocytosis: Jettisoning of cellular material during reprogramming of differentiated cells.
    Jeffrey W Brown, Xiaobo Lin, Gabriel Anthony Nicolazzi, Xuemei Liu, Thanh Nguyen, Megan D Radyk, Joseph Burclaff, Jason C Mills.
      Injury causes differentiated cells to undergo massive reprogramming to become proliferative and repair tissue via paligenosis. Gastric chief cells use paligenosis to reprogram into progenitor-like spasmolytic-polypeptide-expressing metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we notice that sulfated glycoproteins are not only digested during paligenosis but also excreted into the gland. Various genetic and pharmacological approaches show that endoplasmic reticulum membranes and secretory granule cargo are also excreted and that the process proceeds in parallel with but is mechanistically independent of autophagy. Three-dimensional light and electron microscopy demonstrated that excretion occurs via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis." Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion, providing for efficient cellular downscaling.
    Keywords:  CP: Cell biology; Das-1; EPG5; Rab7; secretion; sulfated mucins
    DOI:  https://doi.org/10.1016/j.celrep.2025.116070
  29. J Cell Biol. 2025 Sep 01. pii: e202409024. [Epub ahead of print]224(9):
    The p97 ATPase and its adaptor UBXD8 maintain peroxisome pools by preventing pexophagy.
    Iris D Montes, Suganthan Amirthagunanathan, Rakesh Ganji, Joao A Paulo, Brittany A Ahlstedt, Ly Nguyen, Amit S Joshi, Malavika Raman.
      Peroxisomes perform key metabolic functions in eukaryotic cells. Loss of peroxisome function causes peroxisome biogenesis disorders and severe childhood diseases with disrupted lipid metabolism. One mechanism regulating peroxisome abundance is degradation via selective autophagy (pexophagy). However, the mechanisms regulating pexophagy remain poorly understood in mammalian cells. Here, we find that the evolutionarily conserved AAA-ATPase p97/VCP and its adaptor UBXD8/FAF2 are essential for maintaining peroxisome abundance. From quantitative proteomics studies, we show that loss of UBXD8 affects the abundance of many peroxisomal proteins and that the depletion of UBXD8 results in a loss of peroxisomes. Loss of p97-UBXD8 and inhibition of p97 catalytic activity increase peroxisomal turnover through autophagy and can be rescued by depleting key autophagy proteins and E3 ligases or overexpressing the deubiquitylase USP30. We find increased ubiquitylation of PMP70 and PEX5 in cells lacking UBXD8 or p97. Our findings identify a new role of the p97-UBXD8 in regulating peroxisome abundance by removing ubiquitylated peroxisome membrane proteins to prevent pexophagy.
    DOI:  https://doi.org/10.1083/jcb.202409024
  30. Elife. 2025 Jul 31. pii: RP103945. [Epub ahead of print]14
    Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.
    Cong Chen, Tong-Yao Gao, Hua-Wei Yi, Yi Zhang, Tong Wang, Zhi-Ling Lou, Tao-Feng Wei, Yun-Bi Lu, Tingting Li, Chun Tang, Wei-Ping Zhang.
      Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.
    Keywords:  PINK1; biochemistry; chemical biology; mouse; neurodegeneration; phosphorylation; proteasome; ubiquitin
    DOI:  https://doi.org/10.7554/eLife.103945
  31. Neurosci Lett. 2025 Jul 29. pii: S0304-3940(25)00221-6. [Epub ahead of print] 138333
    Delayed administration of rapamycin inhibits glial scar formation through upregulating matrilin-3 in an autophagy-dependent manner in ischemic stroke.
    Yi Guo, Aiping Qin, Li Sun, Jinzhi He, Yuping Shan, Xinyi Wang, Tongxin Zhang, Min Li, Yuqi Ma, Shigang Qiao, Huiling Zhang.
      Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR inhibitor and an autophagy activator. Although it has neuroprotective effects against acute ischemic stroke, it is unknown whether delayed administration of rapamycin can reduce ischemic stroke-induced pathogenesis such as glial scar formation, independent on its effects of acute administration. We recently reported that matrilin-3, an extracellular matrix component, provides neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation and glial scar formation. Here, in rat models of middle cerebral artery occlusion and reperfusion (I/R), rapamycin was administered for consecutive 7 or 14 days starting at day 1 post-reperfusion; and in an oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced primary astrocyte or human astrocyte injury model, rapamycin was given upon reoxygenation. We found that rapamycin improved I/R-mediated rats' neurological dysfunction, accompanied by reduced glial scar formation and neuronal loss. To our surprise, rapamycin increased the levels of matrilin-3 in the peri-infarct region of rats and in OGD/Re-treated astrocytes associating with restoring autophagic flux. In contrast, the autophagy inhibitors wortmannin and bafilomycin A1 blocked autophagic flux, decreased the levels of matrilin-3 and enhanced glial scar formation, respectively. Overexpression of matrilin-3 significantly reduced the glial scar formation. Mechanistically, rapamycin could decrease the ADAMTS-4 and ADAMTS-5 levels, two hydrolases responsible for the breakdown of matrilin-3, thus upregulating the matrilin-3 levels. Our results reveal that delayed administration of rapamycin suppresses the glial scar formation by upregulating the astrocytic matrilin-3 related to restoring autophagic flux in ischemic stroke.
    Keywords:  ADAMTS-4/5; Astrocytes; Autophagy; Glial scar; Ischemic stroke; Matrilin-3; Rapamycin
    DOI:  https://doi.org/10.1016/j.neulet.2025.138333
  32. Nat Struct Mol Biol. 2025 Jul 25.
    A structural switch reveals how to disarm USP30 and unlock mitophagy.
    Julia C Fitzgerald, Anja Bremm.
      
    DOI:  https://doi.org/10.1038/s41594-025-01640-3
  33. Trends Immunol. 2025 Jul 29. pii: S1471-4906(25)00176-0. [Epub ahead of print]
    Targeting WSTF degradation to resolve chronic inflammation.
    Weiqiong Feng, Wenzhe She, Rong Xiang.
      Chronic inflammation drives diseases like osteoarthritis and MASH, yet its molecular distinction from acute inflammation remains unclear. In a recent Nature study, Wang et al. revealed that chronic stress triggers WSTF degradation via nuclear autophagy, amplifying NF-κB responses. Blocking this pathway attenuates chronic inflammation while sparing acute immunity.
    Keywords:  GABARAP; MASH; WSTF; chronic inflammation; nuclear autophagy; osteoarthritis
    DOI:  https://doi.org/10.1016/j.it.2025.07.009
  34. J Neurophysiol. 2025 Aug 01.
    CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
    Xiaoke Qiu, Shaoda Lai, Yingyi Zhang, Shengtao Huang, Han Li, Junsheng Liu, Yong Huang, Zhinan Zhang.
      The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency towards mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increase mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.
    Keywords:  Depression; FIS1; MFF; mitochondria fragmentation; mitophagy
    DOI:  https://doi.org/10.1152/jn.00523.2024
  35. J Biol Chem. 2025 Jul 25. pii: S0021-9258(25)02375-0. [Epub ahead of print] 110524
    TORC2 and MAPK signaling pathways regulate mitochondrial degradation induced by iron starvation in Schizosaccharomyces pombe.
    Rong Li, Jinjie Shang, Ying Huang.
      Iron is essential for life as it participates in metabolic processes, including DNA synthesis, respiration, and photosynthesis. In this study, we show that iron starvation induced by 2,2'-dithiodipyl (DIP) causes mitochondrial dysfunction, impairs mitochondrial function, including mitochondrial membrane potential (ΔΨm) and respiration, and induces mitochondrial degradation in the vacuole of Schizosaccharomyces pombe. The DIP-induced mitochondrial degradation is independent of components of the core autophagy machinery and the ESCRT machinery examined here. We demonstrate that the target of rapamycin complex 2 (TORC2) and its sole target, the AGC kinase Gad8, and the mitogen-activated protein kinase (MAPK) Sty1 play positive roles in regulating iron starvation-induced mitochondrial degradation. The reduction in the level of mitochondrial degradation in Δgad8 cells could be restored to wild-type-like levels by treating Δgad8 cells with chloramphenicol (CAP) and NaN3, two inhibitors of mitochondrial respiration, and by deleting genes, encoding components important for mitochondrial electron transport chain (ETC). Disruption of Ca2+ signaling through deletion of genes encoding the Ca2+ channel proteins Yam8 and Cch1 and the regulatory subunit of calcineurin Cnb1 also restored mitochondrial degradation in Δgad8 cells. Our results suggest that the Sty1 MAPK participates with TORC2-Gad8 signaling in regulating DIP-induced mitochondrial degradation. Our results also suggest that TORC2-Gad8 signaling regulates iron starvation-induced mitochondrial degradation through regulation of mitochondrial respiration and Ca2+ signaling.
    Keywords:  Sty1; TORC2; calcineurin; mitochondrial degradation; respiration
    DOI:  https://doi.org/10.1016/j.jbc.2025.110524
  36. Methods. 2025 Jul 24. pii: S1046-2023(25)00163-X. [Epub ahead of print]
    A simple, accurate method for the measurement of lysosomal activity.
    Yoshito Iwai, Yuriko Furuya, Yuji Oguro, Keiji Yamamoto.
      Lysosomes are responsible for the degradation of intra- and extracellular components and are thus essential for the quality control of proteins and organelles. Lysosomal dysfunction leads to lysosomal storage diseases, and it is therefore important to identify which types of stress cause functional abnormalities. Lysosomal function is generally evaluated by measuring the enzyme activity of lysosomes with fluorescent dyes. However, fluorescence microscopy can lead to different outcomes due to variations in the field of view, the analysis software used, and the parameter settings. We therefore developed a method that uses only a microplate reader and DQ Green BSA, a dye that emits fluorescence upon lysosomal degradation, to ascertain lysosomal activity. HEK293 cells were treated with DQ Green BSA with or without bafilomycin A1 and lysates extracted using radioimmunoprecipitation buffer. Fluorescence intensities and protein concentrations in the cell lysates were then measured using a microplate reader and the bicinchoninic acid method, respectively, and the fluorescence intensity divided by the protein concentration. Results indicated a significant lysosome inhibitor-induced dose-dependent decrease in the lysosomal activity. The Z'-factor of 0.77 obtained using the proposed method is a significant improvement over the - 0.06 obtained using the conventional method. The versatility of the method was evaluated with different cell types, cell lysis buffers, inhibitors, and protease substrates, with results suggesting that the method works regardless of the cells or reagents used, indicating the relative simplicity and accuracy of the proposed method as compared to the currently utilized method.
    Keywords:  Autophagy-lysosomal pathway; Cell lysate; Experimental design; Fluorescent protein; Lysosomal activity; Microplate reader
    DOI:  https://doi.org/10.1016/j.ymeth.2025.07.008
  37. J Hepatol. 2025 Jul 29. pii: S0168-8278(25)02329-3. [Epub ahead of print]
    A newly revealed signaling pathway may explain the conundrum of how FGF21 simultaneously increases insulin sensitivity and autophagy.
    Timothy Rolph, Morris J Birnbaum.
      
    DOI:  https://doi.org/10.1016/j.jhep.2025.07.002
  38. Acta Biomater. 2025 Jul 28. pii: S1742-7061(25)00557-4. [Epub ahead of print]
    Nanotechnology-targeted modulation of mitophagy in cancer therapy: Progress and challenges.
    Hongyu Yang, Chang Peng, Hanjie Sun, Sen Mu, Aiyang Tong, Siqi Wang, Dongkai Wang, Ji Li.
      The clinical efficacy of current cancer treatments remains insufficient, creating an urgent need to identify new therapeutic targets and combine them with traditional treatment methods. Mitophagy, a crucial mechanism for the intracellular clearance of damaged mitochondria, has shown tremendous potential in cancer therapy. However, accurately and effectively regulating mitophagy remains a significant challenge. In some years, nanoparticle-based drug delivery systems have attracted considerable attention due to their high targeting ability and deep tissue penetration. Therefore, applying nanotechnology to regulate mitophagy may offer new therapeutic strategies for cancer treatment. This review provides a comprehensive overview of the recent advances in the targeted regulation of mitophagy using nanotechnology, including the use of nanoparticle carriers alone or in combination with other cancer therapies. Additionally, we discuss the development of mitophagy, the relevant signaling pathways, the relationship between mitophagy and cancer, drugs that modulate mitophagy, and methods for detecting mitophagy. Finally, we explore the prospects and challenges of using nanotechnology to target and regulate mitophagy in cancer therapy. STATEMENT OF SIGNIFICANCE: This review underscores the therapeutic relevance of mitophagy in cancer, focusing on its selective role in mitochondrial quality control and tumor regulation. Given the challenges in precise mitophagy modulation, we highlight the emergence of nanotechnology based delivery systems as a promising solution. The review covers mitophagy mechanisms, associated pathways, detection techniques, mitophagy modu lating agents, and nanoparticle strategies- both standalone and combinatorial. It further discusses translational opportunities and technical barriers, offering a concise, integrative perspective on how nanomedicine can enable targeted mitophagy interventio n for improved cancer therapy.
    Keywords:  Cancer treatment; Mitophagy; Nano-delivery strategy; Nanomaterials
    DOI:  https://doi.org/10.1016/j.actbio.2025.07.059
  39. Int Immunopharmacol. 2025 Jul 31. pii: S1567-5769(25)01287-1. [Epub ahead of print]163 115296
    CORM-3 mitigates osteoarthritis by anti-inflammation and enhancing autophagy via inhibiting MAPK and mTOR pathways.
    Jianwen Li, Yunqian Zeng, Shiheng Wang, Xin Chen, Hui Huang, Xin Gan, Hao Kang.
       BACKGROUND: Osteoarthritis (OA) is a chronic degenerative disorder marked by progressive degradation of articular cartilage. Inflammation and impairment of autophagy are crucial in OA pathogenesis, leading to chondrocyte dysfunction and disease progression. The therapeutic potential of CORM-3, a carbon monoxide-releasing molecule with anti-inflammatory and autophagy-enhancing properties, remains unexplored in OA.
    METHODS: Chondrocytes were treated with interleukin-1β (IL-1β) to establish an inflammatory model in vitro. The impact of CORM-3 on chondrocyte inflammation, extracellular matrix (ECM) metabolism, and autophagy activity was assessed by RT-qPCR, Western blot, immunofluorescence, and autophagy flow assay. OA was induced in mice to investigate CORM-3's therapeutic potential in vivo through surgical destabilization of the medial meniscus (DMM).
    RESULTS: CORM-3 significantly inhibited the inflammation of chondrocytes and the imbalance of extracellular matrix (ECM) metabolism induced by IL-1β, thereby exerting a chondroprotective effect in vitro. Mechanistically, CORM-3 effectively inhibited the mitogen-activated protein kinase (MAPK) and mTOR signaling pathways. Further, CORM-3 exerted a similar chondroprotective effect with MAPK-IN-1, a MAPK pathway inhibitor, and rapamycin, a specific mTOR inhibitor. Additionally, CORM-3 also restored the impairment of autophagy. Furthermore, 3-Methyladenine (3-MA), an autophagy inhibitor, reversed CORM-3's chondroprotective effect. In vivo, treatment with CORM-3 inhibited cartilage OA-like lesions to mitigate OA progression.
    CONCLUSION: This study identifies that CORM-3 inhibits inflammation, maintains ECM metabolism homeostasis, and restores impaired autophagy via inhibiting the MAPK and mTOR pathways, thereby protecting chondrocytes. In vivo, CORM-3 treatment significantly alleviates OA progression, suggesting its therapeutic potential for OA.
    Keywords:  Autophagy; CORM-3; Inflammation; MAPK; Osteoarthritis; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2025.115296
  40. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251363050
    Membrane Contact Sites in Proteostasis and ER Stress Response.
    Febe Vermue, Aysegul Sapmaz, Ilana Berlin.
      Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes - the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.
    Keywords:  endolysosome; endoplasmic reticulum; membrane contact sites; proteostasis; proteotoxic stress
    DOI:  https://doi.org/10.1177/25152564251363050
  41. Cell Mol Biol (Noisy-le-grand). 2025 Jul 30. 71(7): 1-7
    Modern methods of detecting mitophagy.
    Alexander V Blagov, Andrey Y Vinokurov, Vasily N Sukhorukov, Anton Y Postnov, Elizaveta M Pleshko, Alexander N Orekhov.
      Inhibition of mitophagy is one of the signs of chronic disease pathogenesis. Detection and measurement of mitophagy levels under in vitro and in vivo models provide a better understanding of the role of mitophagy disorder in disease development and serve as prerequisites for creating a clinically applicable system test. The development of such a system is potentially feasible, but taking into account a number of factors that will be discussed in detail in this article. Here it is considered the main models of mitophagy-based test systems and an analysis is carried out showing their advantages and disadvantages. The future potential for the development of mitophagy-based diagnostic test systems is also discussed here.
    DOI:  https://doi.org/10.14715/cmb/2025.71.7.1
  42. Lipids Health Dis. 2025 Jul 30. 24(1): 254
    Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.
    Roshan Javanshad, Wenping Li, Koralege C Pathmasiri, Stephanie M Cologna.
      Niemann-Pick type C (NPC) disease is a devastating, fatal, neurodegenerative disease and a form of lysosomal storage disorder. It is caused by mutations in either NPC1 or NPC2 genes, leading to the accumulation of cholesterol and other lipids in the late endosome/lysosome system, a hallmark of the disease. Due to aberrant lipid trafficking in NPC, various techniques have been employed to study cholesterol and lipid dysregulation. Among them, mass spectrometry (MS)-based lipidomics has emerged as a state-of-the-art approach, providing valuable insights into disease pathophysiology, progression, and therapeutic target development. This review highlights the MS instruments used for lipidomics studies and discusses lipid biomarkers identified using MS in the context of NPC disease. Furthermore, integrating lipidomics with other -omics approaches, and leveraging the power of artificial intelligence, should be prioritized in future studies to holistically understand NPC disease.
    DOI:  https://doi.org/10.1186/s12944-025-02675-7
  43. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  44. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 26. pii: S1388-1981(25)00081-2. [Epub ahead of print] 159673
    Phosphoinositides as regulators of membrane contact sites.
    Håvard S Haukaas, Harald Stenmark.
      Membrane contact sites (MCSs) between the different compartments of the cell play important roles in lipid, protein and ion transfer. Phosphoinositides are crucial for the functions of many MCSs, either as membrane anchors for MCS proteins, or as part of a countertransport mechanism driven by phosphoinositide dephosphorylation in the endoplasmic reticulum. Here we review the involvement of phosphoinositides in MCSs between the endoplasmic reticulum and other organelles such as the plasma membrane, mitochondria, endosomes, lysosomes, autophagosomes and the Golgi complex. These phosphoinositide-containing MCSs mediate transfer of Ca2+, phospholipids, cholesterol, and a motor protein, and thus are of great importance for cellular physiology.
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159673
  45. J Hematol Oncol. 2025 Aug 01. 18(1): 78
    Mitophagy's impacts on cancer and neurodegenerative diseases: implications for future therapies.
    Jason Huang, Vincent Truong Pham, Shaozi Fu, Gang Huang, Ya-Guang Liu, Lei Zheng.
      Substantial evidence supports an inverse relationship between cancer and neurodegenerative diseases (NDDs), but few studies investigate the biological mechanisms underlying this phenomenon. While previous explanations-such as inflammation, reactive oxygen species (ROS), genetic mutations, and cell death-remain significant, they ultimately converge on mitophagy. This review identifies mitophagy as a pivotal factor in the development of both cancer and NDDs, while also evaluating specific mechanisms and processes to clarify how mitophagy connects these opposing disease trajectories. By examining these factors, we aim to uncover the underlying mechanisms that explain the inverse relationship between cancer and NDDs, which will help develop therapeutic strategies that target common factors for both conditions.
    Keywords:  Calcium; Cancer; Cell death; Inflammation; Mitochondrial dysfunction; Mitophagy; Mutations; Neurodegenerative diseases; ROS; Therapeutics
    DOI:  https://doi.org/10.1186/s13045-025-01727-w
  46. Trends Cell Biol. 2025 Jul 29. pii: S0962-8924(25)00151-5. [Epub ahead of print]
    Lessons in longevity from blood stem cells under protein stress.
    André Catic.
      Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into longevity and potential therapeutic strategies. This review examines emerging mechanistic links between proteostasis and HSC fate, concluding with unresolved questions and challenges of the current research.
    Keywords:  aging; autophagy; hematopoietic stem cells (HSCs); proteasome; protein homeostasis (proteostasis); translation control
    DOI:  https://doi.org/10.1016/j.tcb.2025.06.006
  47. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
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