bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–07–26
27 papers selected by
Viktor Korolchuk, Newcastle University
  1. The role of E3 ubiquitin ligases in selective types of macroautophagy.
  2. Atg23 prevents aberrant fusion of Atg9 vesicles during delivery to autophagosome formation sites.
  3. HTLV-1 Tax induces PINK1-PRKN/parkin-dependent mitophagy to mitigate activation of the CGAS-STING1 pathway.
  4. TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.
  5. Disrupted Mitochondrial Quality Control in Atherosclerotic Disease: Mitophagy and Dynamics in Focus.
  6. Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury.
  7. Regulatory role of autophagy in epidermal function.
  8. Cytostatic autophagy: an underappreciated form of autophagy and its ramifications in cancer.
  9. Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.
  10. Global cellular responses to lysosomal damage.
  11. Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.
  12. Cytosolic DNA-induced CGAS-STING1-dependent autophagy promotes SFTSV and EV-71 replication.
  13. The emerging role of ERphagy/reticulophagy in pathogen invasion.
  14. Going viral - Plant selective autophagy swiping left and right on viral infections.
  15. Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
  16. IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.
  17. mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver.
  18. Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
  19. Structural and mechanistic basis for membrane recognition and activation of the vacuolar lipase Atg15.
  20. O-GlcNAc Modification of CaMKII-Mediated Mitophagic Flux Regulation via HSPB8 in Diabetic Cardiomyopathy.
  21. A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.
  22. TBC1D9 and TBC1D9B are ARL8 effectors that modulate exosome secretion through a RAB11A-exocyst pathway.
  23. Is Nuclear mTOR Relevant for Neuronal Dysfunction?
  24. VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
  25. HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
  26. Borrowed scissors for lysosome fission.
  27. Nucleophagy as an emerging therapeutic vulnerability in cancer.
  1. EMBO Rep. 2026 Jul 23.
    The role of E3 ubiquitin ligases in selective types of macroautophagy.
    Monja Müller, Konstanze F Winklhofer, Fulvio Reggiori.
      In contrast to the ubiquitin (Ub)-proteasome-system, which only degrades individual proteins, macroautophagy can eliminate protein complexes or aggregates, organelles and even pathogens. Terms such as mitophagy, aggrephagy, lysophagy and xenophagy have been coined based on the targeted substrate. In Ub-dependent selective macroautophagy, cargo selectivity is specified by E3 Ub ligases that append Ub chains that in turn are recognized by selective autophagy receptors (SARs), driving sequestration into autophagosomes. While several Ub-dependent SARs have been identified and characterized, the E3 Ub ligases that ultimately decide target fate remain poorly studied. In this review, we summarize what is known about the E3 Ub ligases involved in selective macroautophagy, with a particular emphasis on the degradation of mitochondria, protein aggregates, lysosomes and pathogens. A better characterization of these enzymes could improve therapeutic strategies for targeted degradation in acute and chronic diseases.
    DOI:  https://doi.org/10.1038/s44319-026-00887-1
  2. EMBO J. 2026 Jul 20.
    Atg23 prevents aberrant fusion of Atg9 vesicles during delivery to autophagosome formation sites.
    Takumi Kimura, Takayuki Shima, Tetsuya Kotani, Hitoshi Nakatogawa.
      Autophagosome biogenesis depends on the accurate delivery of membrane lipids to the pre-autophagosomal structure. Golgi/endosome-derived Atg9 vesicles provide the membrane seed for this process, but how they are trafficked through the cytoplasm while avoiding inappropriate fusion remains unclear. Here we show that in Saccharomyces cerevisiae, the soluble Atg9-interacting protein Atg23 remains associated with Atg9 vesicles after their biogenesis. This association shields Atg9 vesicles from aberrant SNARE-dependent fusion as they diffuse through the cytoplasm en route to the autophagosome formation site. We further show that upon vesicle arrival at the site, Atg9 phosphorylation by the autophagy initiation kinase Atg1 releases Atg23, facilitating recruitment of the downstream factor Atg2, a lipid transfer protein for membrane expansion. Together, these findings reveal an Atg1-dependent phosphorylation switch that regulates Atg9 vesicle dynamics during autophagosome biogenesis.
    DOI:  https://doi.org/10.1038/s44318-026-00867-0
  3. Autophagy. 2026 Jul 22.
    HTLV-1 Tax induces PINK1-PRKN/parkin-dependent mitophagy to mitigate activation of the CGAS-STING1 pathway.
    Suchitra Mohanty, Sujit Suklabaidya, Nelli Mnatsakanyan, Steven Jacobson, Edward W Harhaj.
      Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit IKBKG/NEMO and directly engages the ubiquitin-dependent PINK1-PRKN/parkin pathway to induce mitophagy. Tax also recruits autophagy receptors CALCOCO2/NDP52 and SQSTM1/p62 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires PRKN to limit the extent of CGAS-STING1 activation and suppress type I interferon (IFN) induction. HTLV-1-transformed T-cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy, and inhibition of PRKN in HTLV-1-transformed cell lines downregulates p19 Gag expression and induces cell death. Collectively, our findings suggest that Tax manipulation of the PINK1-PRKN mitophagy pathway represents a new HTLV-1 immune evasion strategy important for maintaining viral gene expression and cell survival.
    Keywords:  CALCOCO2/NDP52; HTLV-1; IKBKG/NEMO; PINK1; PRKN/Parkin; STING1; mitochondria; mitophagy; reactive oxygen species; tax
    DOI:  https://doi.org/10.1080/15548627.2026.2707897
  4. Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00781-3. [Epub ahead of print]45(7): 117703
    TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.
    Jiamin Huang, Yayu Wang, Yudong Xu, Yanan Wei, Xiang Yin, Junling Li, Yu Zeng, Meiting Chen, Canjun Li, Li Wang, Xiaomei Li, Lili Qu, Chunlei Cang.
      Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.
    Keywords:  CLN7; CP: molecular biology; ERK; HSP90; TTYH3; autophagy; chloride conductance; lysosome; lysosome fusion; mTOR; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2026.117703
  5. JACC Basic Transl Sci. 2026 Jul 23. pii: S2452-302X(26)00144-0. [Epub ahead of print]11(8): 101625
    Disrupted Mitochondrial Quality Control in Atherosclerotic Disease: Mitophagy and Dynamics in Focus.
    Taylor Wilcox, Julie Hansen, Andrew Blanker, Michael E Widlansky.
      Mitochondrial health is essential for maintaining cardiac function, and mitophagy-the selective degradation of damaged mitochondria-is central to maintenance of mitochondrial quality. In this review, we focus on the role of mitophagy in atherosclerotic disease, exploring both canonical and noncanonical pathways. We aim to highlight how proper regulation of mitophagy supports cardiac health, while imbalances in this process can contribute to the onset and progression of cardiovascular conditions. In addition, we examine the cardioprotective potential of mitophagy in the context of disease and discuss its close relationship with mitochondrial dynamics, particularly as they relate to both macrovascular and microvascular dysfunction. Finally, we identify current gaps in knowledge and outline key questions that remain for the field to address, with the goal of guiding future research in this critical area of cardiovascular biology.
    Keywords:  atherosclerotic disease; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1016/j.jacbts.2026.101625
  6. Aging Cell. 2026 Aug;25(8): e70644
    Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury.
    Yu Xiang, Ying Fu, Zhiwen Liu, Yu Han, Wenwen Wu, Juan Cai, Dongshan Zhang, Zheng Dong.
      Sepsis-associated acute kidney injury (SA-AKI) is a common and devastating disease that has a significantly higher incidence and greater severity in elderly patients, but the molecular basis underlying SA-AKI in the elderly is largely unknown. Recent studies have proved autophagy as an intrinsic protective mechanism against AKI; however, the role and regulation of autophagy in aging kidneys remain unclear. Here we demonstrate that defective autophagy activation in aging kidneys is a key to their susceptibility to SA-AKI. In our experiments, the ability of autophagy activation was impaired in aging kidneys in response to SA-AKI in mice. In vitro, activation of autophagy with TAT-Beclin-1 peptide mitigated lipopolysaccharide (LPS)-induced apoptosis and inflammation in senescent renal proximal tubular cells. Single-cell sequencing revealed significant age-related alterations in autophagy-associated genes in septic AKI, including TFEB. Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage. Moreover, in vivo treatment with the curcumin analog C1 (a TFEB activator) enhanced autophagic function in aging kidneys and reduced LPS-induced AKI. These results demonstrate the defective autophagy activation in aging kidneys, which contributes to the SA-AKI sensitivity and susceptibility in the elderly, suggesting a therapeutic strategy by enhancing autophagy.
    Keywords:  TFEB; acute kidney injury; aging; autophagy; sepsis
    DOI:  https://doi.org/10.1111/acel.70644
  7. J Dermatol Sci. 2026 Jul 13. pii: S0923-1811(26)00120-9. [Epub ahead of print]
    Regulatory role of autophagy in epidermal function.
    Dongyun Lei, Shiying Li, Litao Zhang, Guoqiang Zhang, Mao-Qiang Man.
      Autophagy, a highly conserved cellular degradation process, is essential for maintaining cellular homeostasis and responding to stress. Recent studies have highlighted the importance of autophagy in regulating epidermal functions, including keratinocyte differentiation and proliferation, epidermal lipid synthesis, inflammation, and antioxidation. In the epidermis, autophagy facilitates the removal of damaged organelles and protein aggregates, ensuring proper keratinocyte maturation and stratum corneum formation. Dysregulation of autophagy has been linked to various dermatological conditions, such as psoriasis, atopic dermatitis, and skin aging. Furthermore, autophagy modulates the inflammatory response in the skin by regulating cytokine production and immune cell activity. This review summarizes evidence supporting the role of autophagy in epidermal function and emphasizes its potential as a therapeutic target. Additionally, approaches to enhance autophagy are discussed.
    Keywords:  autophagy; epidermal lipids; epidermal permeability barrier; keratinocyte differentiation
    DOI:  https://doi.org/10.1016/j.jdermsci.2026.07.003
  8. Autophagy. 2026 Jul 24.
    Cytostatic autophagy: an underappreciated form of autophagy and its ramifications in cancer.
    Ahmed M Elshazly, Aya A Elzahed, Shady Allam, Daniel J Klionsky, Senthil K Radhakrishnan, David A Gewirtz.
      Macroautophagy/autophagy is a well-established homeostatic mechanism that contributes to the integrity of multiple regulatory biological activities including but not limited to the gastro-intestinal tract and cognitive integrity. Autophagy also plays a central role in tissue regeneration, metamorphosis and development whereas defects in autophagy are associated with a wide range of disorders including metabolic diseases such as diabetes, organ pathophysiologies including liver, lung and heart disease, cancer, and microbial infection. In the field of cancer therapy, most research efforts have focused on cytoprotective autophagy, with substantial preclinical and clinical studies designed to interrogate the outcomes of pharmacologically (or genetically in preclinical work) inhibiting autophagy to enhance the efficacy of chemotherapeutic agents. There is lesser but nevertheless robust evidence for the cytotoxic function of autophagy while our laboratory and a few others have identified the nonprotective form of this cellular response. However, cytostatic autophagy, a distinct functional outcome of autophagy characterized by sustained proliferative arrest, has remained relatively underexplored. Cytostatic autophagy can be defined as a cellular condition in which autophagy activation coincides with durable proliferative arrest, and in which genetic or pharmacological inhibition of autophagy relieves the growth-arrest phenotype without inducing overt cytotoxicity. In this review, we provide the first comprehensive synthesis of the scientific literature addressing cytostatic autophagy, tracing its historical development and consolidating the experimental evidence that led to its current conceptual definition. We further discuss the molecular mechanisms underlying cytostatic autophagy, including the selective degradation of key cell-cycle regulators and the interplay between autophagy and senescence-associated signaling pathways.
    Keywords:  Autophagy; cancer; cell cycle; cytostasis; senescence
    DOI:  https://doi.org/10.1080/15548627.2026.2709937
  9. J Biochem. 2026 Jul 24. pii: mvag058. [Epub ahead of print]
    Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.
    Natsumi Sakata, Takaaki Akaike, Hozumi Motohashi.
      Supersulfides, a class of catenated sulfur-containing biomolecules, are increasingly recognized as key regulators of redox signaling, mitochondrial function, and inflammatory responses. Recent evidence suggests that lysosomes, central organelles for intracellular degradation and nutrient sensing, are closely linked to supersulfide metabolism through lysosomal acidification, cysteine metabolism, and autophagy. Conversely, supersulfides modulate lysosomal activity and inflammatory responses. This review summarizes recent progress in supersulfide biology and lysosomal regulation and discusses evidence supporting functional interactions between these systems. We propose the lysosome-supersulfide axis as a new concept in cellular homeostasis and metabolic regulation.
    Keywords:  Amino acids; autophagy; cysteine; lysosome; supersulfides
    DOI:  https://doi.org/10.1093/jb/mvag058
  10. Curr Biol. 2026 Jul 20. pii: S0960-9822(26)00655-X. [Epub ahead of print]36(14): R807-R820
    Global cellular responses to lysosomal damage.
    Jingyue Jia.
      Lysosomes are membrane-bound organelles that orchestrate a wide range of cellular processes, including degradation, metabolism, signaling, gene regulation and quality control, while interacting with other organelles, thereby profoundly shaping cellular homeostasis and fate. Lysosomal membrane integrity is highly vulnerable to a broad spectrum of physiological and pathological insults, acting as both a cause and a consequence of diverse human conditions, including neurodegeneration, cancer, infectious disease and aging. Understanding the mechanisms by which cells respond to lysosomal damage is therefore of critical importance. Recent studies have revealed that cells deploy sophisticated damage response mechanisms locally to repair, remove, and replace damaged lysosomes. In contrast, how local lysosomal damage triggers global cellular responses is only beginning to be understood. This review summarizes recent conceptual advances in global cellular responses to lysosomal damage, encompassing translational, metabolic and transcriptional adaptations, and highlights their crucial roles in restoring cellular homeostasis and shaping outcomes in health and disease.
    DOI:  https://doi.org/10.1016/j.cub.2026.05.050
  11. Mol Microbiol. 2026 Jul 19.
    Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.
    Suryansh Rajput, Pragya Mehra, Rohini Nandi, Raksha Devi, Eisha Pandey, Aastha Varshney, Satish Mishra.
      Autophagy is a highly conserved degradative and recycling pathway essential for maintaining cellular homeostasis. Although its molecular machinery is well characterized in yeast and mammalian systems, it is less studied in the early-diverging apicomplexan parasite Plasmodium, the causative agent of malaria. Plasmodium possesses a reduced yet functional repertoire of autophagy-related (ATG) proteins, suggesting adaptations of this pathway to parasite-specific biology. Among these, ATG8, a ubiquitin-like protein, has emerged as a central marker and key effector of plasmodial autophagy. Its branched localization and association with the relict plastid (apicoplast) membrane indicate roles beyond canonical degradative autophagy, particularly in organelle maintenance and biogenesis. ATG7, an essential E1-like enzyme, activates ATG8 and facilitates its lipidation, thereby regulating organelle turnover and development. This process is further supported by a conserved conjugation system involving ATG3 (E2-like enzyme) and the ATG12, ATG5, ATG16 complex, functioning as a ligase to enable ATG8 membrane association. ATG4, a cysteine protease, is critical for recycling lipidated ATG8 and maintaining its cytosolic pool, while the homolog Otu can partially compensate for its function. ATG18 also plays an important role in apicoplast biogenesis and maintenance. Collectively, these findings highlight both canonical and non-canonical roles of autophagy proteins in Plasmodium, driving metabolic reprogramming, intracellular remodeling, and stage-specific differentiation, and support their potential as targets for new antimalarial therapies.
    Keywords:   Plasmodium ; ATG8; apicoplast; autophagy; drug resistance; non‐canonical autophagy
    DOI:  https://doi.org/10.1111/mmi.70096
  12. Autophagy. 2026 Jul 23. 1-15
    Cytosolic DNA-induced CGAS-STING1-dependent autophagy promotes SFTSV and EV-71 replication.
    Xiao-Lan Gu, Qiao Liu, Wen-Kang Zhang, Bang Li, Li-Na Yan, Xue-Jie Yu.
      The CGAS-STING1 pathway is an innate immune system that can detect double-stranded DNA in the cytoplasm and trigger antiviral immune responses. Increasing evidence indicates that CGAS-STING1 signaling can induce autophagy; however, the activation and potential role of the CGAS-STING1-dependent autophagy during RNA virus infection remain unclear. Here, we initially observed that cytosolic DNA acts as a potent inducer of CGAS-STING1-dependent autophagy. Unexpectedly, pre-activation of this pathway via DNA-CGAS-STING1 (1-340) transfection significantly promoted the replication of RNA viruses tested including SFTSV and enterovirus 71 (EV-71). Using SFTSV as a model to investigate the physiological trigger during infection, we demonstrated that SFTSV induces mitochondrial damage, leading to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm. This endogenous mtDNA activates CGAS-STING1-dependent autophagy, which SFTSV then exploits for its replication. Indeed, depletion of mtDNA abolishes SFTSV-induced autophagy and impairs viral replication. Mechanistically, the SFTSV nucleoprotein directly interacts with STING1, hijacking STING1-derived membranes from the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and Golgi apparatus to form its replication platform. Our study reveals a new host anti-RNA virus strategy, namely activating CGAS-STING1-dependent autophagy through cytosolic DNA, as well as the mechanism by which SFTSV hijacks CGAS-STING1-dependent autophagy for viral replication.Abbreviations: CGAS: cyclic GMP-AMP synthase; ER: endoplasmic reticulum; ERGIC: endoplasmic reticulum-Golgi intermediate compartment; EV-71: enterovirus 71; EtBr: ethidium bromide; Gn: glycoproteins N; IFN-I: type I interferon; KO: knockout; MOIs: multiplicities of infection; NP: nucleoprotein; NSs: non-structural proteins; ROS: reactive oxygen species; SFTSV: Severe fever with thrombocytopenia syndrome virus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; VDAC1: voltage dependent anion channel 1; WT: wild-type; gDNA: genomic DNA; mtDNA: mitochondrial DNA.
    Keywords:  Autophagy; CGAS; SFTSV; STING1; host-pathogen interaction; mtDNA
    DOI:  https://doi.org/10.1080/15548627.2026.2704441
  13. Autophagy. 2026 Aug;22(8): 1743-1744
    The emerging role of ERphagy/reticulophagy in pathogen invasion.
    Damian Gatica, Daniel J Klionsky.
      In recent years ERphagy, the selective autophagic degradation of the endoplasmic reticulum (ER), has emerged as a key selective autophagic pathway involved not only in the recycling of the ER, but also in preventing the replication of viruses and bacteria. The mechanisms by which ERphagy achieves this do not seem immediately related to canonical xenophagy pathways and could provide a new avenue for therapeutic targets to combat pathogenic infections. In this editor's corner we briefly summarize the ways ERphagy is involved in pathogen infection, highlighting the potential ERphagy has as an understudied innate immune response pathway.Abbreviation: IFN-I: type I interferon; LPS: lipopolysaccharide; STING1: stimulator of interferon response cGAMP interactor 1.
    Keywords:  Bacteria; FAM134B; endoplasmic reticulum; virus; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2661121
  14. Curr Opin Plant Biol. 2026 Jul 22. pii: S1369-5266(26)00073-7. [Epub ahead of print]93 102930
    Going viral - Plant selective autophagy swiping left and right on viral infections.
    Jens Christian Mülders, Marion Clavel.
      Selective autophagy has emerged as a central interface in plant-virus interactions, acting at once as an antiviral defense, a proviral vulnerability, and a regulator of host immune homeostasis. In plants, autophagy can directly target viral proteins, replication complexes, and even entire virions for degradation, while viruses have evolved diverse strategies to exploit, evade, or repurpose the autophagy machinery. Recent work has revealed an expanding repertoire of plant- and virus-encoded selective autophagy receptors, as well as unexpected roles for autophagy in restraining excessive immune activation and tissue damage during infection. These findings challenge a binary classification of autophagy as either antiviral or proviral. Here, we synthesize recent advances in the field and propose a conceptual framework in which multiple selective autophagy pathways operate in parallel during viral infection, each targeting distinct viral or host components and collectively shaping infection outcomes.
    DOI:  https://doi.org/10.1016/j.pbi.2026.102930
  15. Nat Cell Biol. 2026 Jul 20.
    Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
    Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.
      Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.
    DOI:  https://doi.org/10.1038/s41556-026-02010-x
  16. Autophagy. 2026 Jul 23.
    IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.
    Kai-Po Chen, Tz-Chuen Ju.
      Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.
    Keywords:  Autophagy-lysosomal pathway (ALP); glycogen synthase kinase 3B (GSK3B); huntington disease (HD); interleukin 17A (IL17A); transcription factor E3 (TFE3)
    DOI:  https://doi.org/10.1080/15548627.2026.2707895
  17. Sci Adv. 2026 Jul 24. 12(30): eaec0131
    mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver.
    Aishwarya Sahasrabudhe, Chanté R Guy, Audrey Jacq, Chieh-Wen Ho, Ben J Greenwell, Jerome S Menet.
      Rhythmic gene expression is essential to the daily organization of biological processes. While cycling transcriptomes are regulated by circadian clocks present in nearly every cell, accumulating evidence indicates that they can also be initiated by rhythmic food-driven systemic signals independently of circadian clocks. The underlying mechanisms remain however largely unknown. Here, we show that signaling through the nutrient-sensing kinase mechanistic target of rapamycin (mTOR) is both necessary and sufficient to mediate food-driven hepatic rhythmic gene expression, rhythmic regulation of the liver metabolome, and endoplasmic reticulum stress response. Acute inhibition of mTOR before the active phase desynchronizes the phase of mTOR-driven rhythmic genes without affecting clock-controlled rhythmic genes, indicating that alignment of rhythmic mTOR activity to the circadian cycle is critical for overt cycling transcriptomes. These findings may explain how misalignment between clock and systemic signals contributes to disease and underscore the use of mTOR inhibitors for resynchronizing system-driven rhythms and alleviating circadian rhythm disorders.
    DOI:  https://doi.org/10.1126/sciadv.aec0131
  18. Cell Signal. 2026 Jul 24. pii: S0898-6568(26)00420-1. [Epub ahead of print] 112763
    Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
    Mia Simons Weston, Marta Dominguez Prieto, Nicoleta Moisoi.
      Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signalling to senescence remains incompletely understood. Here, we investigated the interplay between mtQC pathways and cellular stress responses in DNA damage-induced senescence using mouse embryonic fibroblasts (MEFs). MEFs deficient in the mitochondrial protease HtrA2 (proteostasis), the transcription factor Chop (integrated stress response; ISR) or the mitophagy regulator Pink1 were exposed to three mechanistically distinct DNA-damaging agents: bleomycin, etoposide and doxorubicin. Senescence was characterised using multiple complementary markers, including the proportion of high senescence-associated β-galactosidase-positive cells, nuclear size, total and nuclear p21 abundance, and transcriptional analysis of p16, p21 and genes associated with cell-cycle regulation and stress signalling. Mitochondrial dysfunction through mtQC impairment enhanced sensitivity to senescence with HtrA2 and Pink1 loss promoting increased senescence under DNA damage. Although DNA damage response (DDR) was activated as seen by changes in p21 homeostasis, this did not always correlate with senescence levels, which indicates that DDR alone cannot account for all senescence characteristics. The ISR played a modulatory role in the senescence induction, with Chop loss of function reducing senescence induction following DNA damage despite DDR activation. The different DNA damaging drugs produced different senescence outcomes, thus highlighting the importance of the stressor context in addition to the cellular homeostasis mechanisms in the overall senescence profile. This approach allowed, for the first time, to identify senescence subtypes dependent of mtQC and ISR integrity in the context of genotoxic stress.
    Keywords:  Genotoxic stress; Integrated stress response; Mitochondria quality control; Senescence subtypes
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112763
  19. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2601290123
    Structural and mechanistic basis for membrane recognition and activation of the vacuolar lipase Atg15.
    Tomoko Kawamata, Nobuo N Noda, Michiko Sasaki, Yoshinori Ohsumi, Yuji Sakai.
      Atg15 is a vacuolar phospholipase B essential for the degradation of intravacuolar vesicles such as autophagic bodies. Despite its central role in cellular membrane turnover, the molecular basis of how Atg15 is activated and acts on internal membranes has remained elusive. Here, by combining all-atom and coarse-grained molecular dynamics (MD) simulations with in vitro and in vivo analyses, we elucidate the structural and mechanistic principles underlying Atg15 activation and substrate recognition. Our simulations revealed that disulfide bonds are critical for maintaining the structural integrity of the catalytic core, while the C-terminal region locks the catalytic center in a closed state that prevents activation. Membrane binding induces a transition to an open state, enabling catalysis. Through MD-guided mutational analysis, we identified three regions crucial for catalytic locking, membrane binding, and substrate recognition, and experimentally confirmed that mutations in these regions inhibit activity. Furthermore, Atg15 preferentially associates with positively curved membranes, providing a potential basis for its preferential action on internal vesicular membranes. These findings suggest that Atg15's activity is controlled through multiple regulatory layers to ensure safe and preferential membrane degradation.
    Keywords:  autophagic body; autophagy; membrane degradation; molecular dynamics simulation; phospholipase
    DOI:  https://doi.org/10.1073/pnas.2601290123
  20. Clin Sci (Lond). 2026 Jul 22. pii: CS20260408. [Epub ahead of print]
    O-GlcNAc Modification of CaMKII-Mediated Mitophagic Flux Regulation via HSPB8 in Diabetic Cardiomyopathy.
    Yanjuan Jiang, Kaibo Hu, Zhaowei Luo, Huiwen Duan, XinRui Qi, Xuehong Zheng, Jing Zhang, Fang Zou, Xia Cai, Liyan Niu, Peng Yu, Xiaoyang Lai.
       BACKGROUND: In the diabetic heart, hyperglycemia can augment the covalent modification of Ca2+-calmodulin-dependent protein kinaseII (CaMKII) by O-linked N-acetylglucosamine (O-GlcNAc). Concurrently, mitophagy serves as a crucial link in diabetic myocardial injury. The association between these two processes in diabetic cardiomyopathy (DCM) remain to be elucidated. Methods: A rat model of type 1 diabetes was constructed via a single intraperitoneal injection of streptozotocin (STZ; 50 mg/kg). The regulatory mechanism by which O-GlcNAc-modified CaMKII affects mitophagy was determined via bioinformatics analysis and coimmunoprecipitation. Results: At 12 weeks after STZ induction, the rats presented with decreased cardiac function and myocardial injury, accompanied by increased O-GlcNAc modification of CaMKII and significant accumulation of the autophagy markers LC3II/I and P62. Electron microscopy showed an increase in damaged mitochondria and autophagosomes, suggesting that mitophagic flux was inhibited. Bioinformatics analysis identified heat shock protein β-8 (HSPB8) as a crucial autophagy-related protein downstream of CaMKII. The findings confirmed that the adenovirus overexpressing HSPB8 was capable of ameliorating the cardiomyocyte injury induced by high glucose both in vivo and in vitro, effectively facilitating mitophagic flux. An elevation in O - GlcNAc enhances the interaction between CaMKII and HSPB8, exacerbating the inhibitory effect on autophagosome degradation. In contrast, O - GlcNAc inhibitors can effectively mitigate this inhibitory condition. Conclusions: In diabetic rats, an increase in O-GlcNAc can facilitate the binding of its substrate CaMKII to HSPB8, thereby suppressing mitophagic flux and exacerbating myocardial injury.
    Keywords:  CaMKII; HSPB8; O-linked N-acetylglucosamine; autophagy; diabetic cardiomyopathy
    DOI:  https://doi.org/10.1042/CS20260408
  21. Adv Sci (Weinh). 2026 Jul 23. e76778
    A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.
    Qingjian Xie, Yanbo Zhu, Wenhua Jiang, Haobo Xie, Yaojia Li, Mengjie Hu, Kezheng Li, Huan Yu, Yixuan Pan, Chaoyi Jiang, Xueqin Song, Dongsheng Fan, Binbin Deng.
      Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.
    Keywords:  OPTN; PF4; SOD1; amyotrophic lateral sclerosis; mitophagy; proteostasis
    DOI:  https://doi.org/10.1002/advs.76778
  22. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2527864123
    TBC1D9 and TBC1D9B are ARL8 effectors that modulate exosome secretion through a RAB11A-exocyst pathway.
    Ganesh Vilas Shelke, Chad D Williamson, Tal Keren-Kaplan, Juan S Bonifacino.
      Multivesicular endosomes (MVEs) are endolysosomal compartments containing intraluminal vesicles (ILVs) that follow two alternative pathways: fusion with lysosomes, leading to ILV degradation, or fusion with the plasma membrane, resulting in ILV secretion as exosomes. The mechanisms governing this fate decision have only recently begun to be elucidated. Previous work showed that the Biogenesis of lysosome related organelles complex-one-related complex (BORC) and the small guanosine triphosphatase (GTPase) ARL8 promote MVE-lysosome fusion through the ARL8 effector homotypic fusion and protein sorting complex (HOPS), thereby diverting MVEs from exosome secretion. Here, we identify TBC1D9 and TBC1D9B as ARL8 effectors that further suppress exosome release. Acting as GTPase-activating proteins, these proteins drive RAB11A inactivation and dissociation from endolysosomes. This reduces recruitment of the RAB11A effector exocyst complex, preventing MVE fusion with the plasma membrane. These findings thus define a BORC-ARL8-TBC1D9/TBC1D9B axis that further attenuates exosome secretion by blocking MVE-plasma membrane fusion.
    Keywords:  endosomes; exosomes; lysosomes; membrane fusion; small GTPases
    DOI:  https://doi.org/10.1073/pnas.2527864123
  23. J Neurochem. 2026 Jul;170(7): e70528
    Is Nuclear mTOR Relevant for Neuronal Dysfunction?
    Shiwani Kumari, Roberto Pagano, Katarzyna Orzol, Jacek Jaworski.
      The mammalian target of rapamycin (mTOR) is a key regulator of neuronal development, metabolism, and plasticity, and its dysregulation is linked to many neurological disorders. Most studies have focused on cytoplasmic mTOR, yet mTOR is also present in the nucleus. In non-neuronal cells, nuclear mTOR has been linked to transcription, chromatin organization, and RNA metabolism. In neurons, its role remains largely unknown. Here, we present a focused Perspective on nuclear mTOR in the nervous system. We briefly summarize the best-established nuclear functions of mTOR, drawing mainly on evidence from non-neuronal cells. We then reanalyze published mTOR interactome datasets to assess whether these mechanisms may be relevant to neurons. Repeated links were observed to nuclear processes, particularly transcription, chromatin regulation, RNA processing, and DNA repair. Similar patterns were observed for gene sets associated with neurodevelopmental and neurodegenerative disorders. However, these associations are correlative and do not establish causality. Based on these findings, we propose a set of testable predictions and experimental approaches to directly examine nuclear mTOR function in neurons, including selective perturbation of its nuclear activity and analysis of gene expression and RNA processing. A key open question is whether nuclear mTOR has a functional role in neurons beyond its well-established cytoplasmic activities. This Perspective summarizes current evidence, highlights key gaps, and outlines directions for future studies on nuclear mTOR in neuronal function and disease.
    Keywords:  gene expression regulation; mTOR signaling; neuronal dysfunction; neuronal physiology; nuclear mTOR
    DOI:  https://doi.org/10.1111/jnc.70528
  24. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123
    VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
    Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.
      Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.
    Keywords:  VAMP7; glia; mitochondrial dynamics
    DOI:  https://doi.org/10.1073/pnas.2603069123
  25. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2619864123
    HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
    Jiamin Yi, Qin Yang, Chunzhuang Zhou, Yunfei Zhu, Yingfeng Tu, Lin Zhao, Min Tang, Junhong Qin, Tao Long, Tianxing Li, Ping Li, Zikang Gong, Qilin Wang, Xin Yong, Da Jia.
      The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify an AMBRA1-RMC1-HUWE1 signaling axis that directs HUWE1-mediated ubiquitination to mitochondria to regulate neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, and H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, AMBRA1 acts as a mitochondrial scaffold that recruits RMC1, enabling HUWE1 localization to mitochondria through direct interaction with RMC1. Disruption of this recruitment by disease-associated HUWE1 variants prevents mitochondrial targeting and impairs mitochondrial substrate ubiquitination. Notably, Urolithin A treatment ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Together, our findings define an AMBRA1-organized mitochondrial recruitment pathway in which RMC1 links HUWE1 to mitochondria, explain noncatalytic HUWE1-associated XLID, and suggest mitochondrial quality-control enhancement as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1073/pnas.2619864123
  26. Nat Cell Biol. 2026 Jul 20.
    Borrowed scissors for lysosome fission.
    Shawn M Ferguson.
      
    DOI:  https://doi.org/10.1038/s41556-026-02028-1
  27. Autophagy. 2026 Jul 24. 1-3
    Nucleophagy as an emerging therapeutic vulnerability in cancer.
    Sara Tribble, Kristijan Ramadan.
      Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in homologous recombination-deficient (HRD) cancers by trapping PARP1 on DNA, causing replication fork collapse, DNA double-strand breaks, and ultimately cell death. However, primary and acquired resistance to PARPi remains a major clinical challenge. Here, we describe a previously unrecognized mechanism for the resolution of cytotoxic trapped PARP1 through TEX264-mediated nucleophagy. We identify the p97-TEX264-nucleophagy axis as a critical pathway for the clearance of trapped PARP1 and a promising therapeutic target for overcoming PARPi resistance in HRD cancers.
    Keywords:  Homologous recombination deficiency; PARP1 trapping; TEX264; nucleophagy; synthetic lethality; therapeutic resistance
    DOI:  https://doi.org/10.1080/15548627.2026.2706401
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