bims-auttor 2026-08-16 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–08–16
37 papers selected by
Viktor Korolchuk, Newcastle University

TBK1 puts the brakes on IRGQ-mediated autophagy.
Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
Wiring autophagy: Neural circuits regulate lysosomal homeostasis in muscle.
An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Retinal ganglion cell autophagy: a housekeeper essential for neuronal homeostasis and survival.
p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
Established and emerging roles of lysosomal dysfunction in cardiac aging.
Regulation and roles of mammalian mitophagy.
FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
Autophagy in Melanoma: Molecular Mechanisms and Therapeutic Perspectives.
Autophagy in Osx1-Cre-targeted cells is essential for development, growth, and maintenance of bone.
A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
Mechanism of Autophagic Extracellular Vesicles Revealed.
AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.
New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.
Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
TRPM2 Promotes Lipophagy Through TFEB and LAL in HFD-Fed Mice.
Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias.
Senecavirus a 3C protease cleaves RETREG1 to antagonize ER-phagy and promote viral replication via endoplasmic reticulum calcium signaling.
ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.
Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.
Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.
α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.
Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.
Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.
Natural Bioactive Compounds Targeting Key Hallmarks of Aging: Functional Food Potential of Spermidine, Fisetin, Berberine, and Urolithin A.
Simulated microgravity induces a time-dependent shift from autophagy to apoptosis in osteoblasts, validated by TSPO, ATG12, and BNIP3L expression in vivo.
The E. coli High-Pathogenicity Island Downregulates PI3K/Akt/mTOR Expression and Induces Autophagy in the Mouse Intestine.
The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.
PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.
Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.
Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.
ZNF143 suppresses mitophagy to drive MASLD progression by regulating SMURF1/TRPV1 axis.

Autophagy. 2026 Aug 10.

TBK1 puts the brakes on IRGQ-mediated autophagy.

Lina Herhaus.

  Selective autophagy requires cargo receptors that not only recognize substrates but also coordinate their engagement with the autophagy machinery. Our findings identify IRGQ as a signaling-sensitive organizer of autophagy initiation rather than a passive cargo adaptor. IRGQ contains two distinct LC3-interacting region motifs: one with unusual selectivity for GABARAPL2 and another that supports broader interaction with LC3-family proteins. Proteomics, co-immunoprecipitation and imaging place the IRGQ-GABARAPL2 complex at the interface between hATG8 proteins and core autophagy-initiation components, including ATG3, ATG7, ULK1 and ATG13. Consistently, IRGQ expression promotes hATG8 lipidation and correlates with increased LC3B puncta, supporting a model in which IRGQ nucleates a local initiation hub that couples cargo recognition to autophagosome formation. Unexpectedly, this hub is negatively regulated by TBK1. TBK1-dependent phosphorylation of GABARAPL2 at serine 10 does not broadly disrupt canonical LDS-mediated interactions, but selectively destabilizes the IRGQ-GABARAPL2 complex and weakens association with autophagy-initiation factors. This phosphorylation is induced during selective-autophagy-associated conditions, including mitophagy, xenophagy and IFNγ treatment, but not during starvation-induced bulk autophagy. Functionally, GABARAPL2 S10 phosphorylation leaves LC3 and p62 bulk-autophagy readouts largely intact while reducing GABARAPL2 flux and impairing lysosomal delivery of HLA, an IRGQ cargo. Thus, TBK1 acts as a context-dependent negative regulator of a receptor-specific autophagy axis, revealing that kinase signaling can tune selective autophagy by controlling the stability and lifetime of receptor-centered initiation hubs.

Keywords:  Autophagy; GABARAPL2; HLA quality control; IRGQ; TBK1; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2716595
J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02302-1. [Epub ahead of print] 113430

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.

Johan Panek, Edward Fielder, Congsing Sun, Steph Crabtree, Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura Booth, Wyatt Yue, Gavin Richardson, Lauren Holder, Gavin J Miller, Jóhannes Reynisson, Sovan Sarkar, Viktor I Korolchuk.

  Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.

Keywords:  Autophagy; Mitophagy; Niemann-Pick type C1 disease; Oligomerisation; ROS; p62

DOI:  https://doi.org/10.1016/j.jbc.2026.113430
Dev Cell. 2026 Aug 12. pii: S1534-5807(26)00277-7. [Epub ahead of print]61(8): 1593-1594

Wiring autophagy: Neural circuits regulate lysosomal homeostasis in muscle.

Min Chen, Congcong He.

Autophagy is commonly viewed as a cell-autonomous degradative process governed by intracellular metabolic and stress signals,1 but how autophagy is coordinated across tissues in multicellular organisms remains unclear. Zheng et al. 2 identify two parallel neuronal circuits that non-cell-autonomously regulate muscle autophagy in C. elegans, revealing an unexpected role for the nervous system in orchestrating peripheral autophagy.

DOI: https://doi.org/10.1016/j.devcel.2026.07.008
Autophagy. 2026 Aug 13. 1-11

An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.

Dale P Corkery, Yao-Wen Wu.

  Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death. Recent advances identify membrane ATG8 conjugation (atg8ylation) as a key process that links damage detection to coordinated lysosomal repair, removal, and regeneration. Beyond its canonical role in macroautophagy, membrane atg8ylation also occurs on preexisting, non-autophagosomal single membranes through Conjugation of ATG8s to Single Membranes (CASM), positioning this pathway as a rapid response to membrane stress. Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling. These ligases convert damage signals into spatially restricted membrane atg8ylation, generating a membrane-associated platform that coordinates multiple downstream pathways. These include ESCRT-dependent membrane repair, ER-lysosome lipid transfer, membrane tubulation, and stress granule formation. When repair fails, membrane atg8ylation regulates lysophagy and activates lysosomal biogenesis and regeneration to restore lysosomal homeostasis. These emerging findings define membrane atg8ylation as a central organizer of membrane quality control rather than a pathway merely confined to macroautophagy. In this review, we summarize the current understanding of how membrane atg8ylation detects lysosomal damage and how this pathway coordinates other lysosomal quality control mechanisms to maintain lysosomal integrity.

Keywords:  CASM; Lysosome; lysosomal membrane integrity; membrane atg8ylation; noncanonical autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2704442
Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):

The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.

Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.

Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy

DOI:  https://doi.org/10.3390/cells15151371
Autophagy Rep. 2026 ;5(1): 2710457

Retinal ganglion cell autophagy: a housekeeper essential for neuronal homeostasis and survival.

Yogapriya Sundaresan, Gulab S Zode.

  Retinal ganglion cells (RGCs) are the sole projection neurons of the retina and the only direct link between retinal circuitry and the brain. Maintaining this lifelong connection requires constitutive autophagy to preserve organelle quality control and neuronal homeostasis. Although autophagy has been widely studied following ocular hypertension and optic nerve injury, its physiological role in healthy RGCs has remained unclear. We have recently revealed that basal autophagy is highly active in RGCs and that conditional deletion of Atg5 or Atg7 is sufficient to induce progressive RGC dysfunction, optic nerve degeneration, and neurodegeneration. Autophagy deficiency caused the accumulation of swollen mitochondria, distended endoplasmic reticulum, fragmented Golgi, synaptic vesicles, and incomplete autophagosomes accompanied by increased p62 and LC3B levels. These findings establish basal autophagy as an essential housekeeping mechanism that preserves organelle quality control and long-term RGC integrity.

Keywords:  ATG5; ATG7; autophagy; conditional knockout; neurodegeneration; neuronal homeostasis; organelle accumulation; retinal ganglion cells

DOI:  https://doi.org/10.1080/27694127.2026.2710457
FEBS J. 2026 Aug 11.

p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.

Jun-Ichi Sakamaki, Masaaki Komatsu.

  Upon exposure to stress, cells activate a variety of stress-response and quality-control mechanisms to maintain homeostasis. Dysregulation of these processes is implicated in numerous diseases, including cancer, liver disorders, and neurodegenerative diseases. p62/Sequestosome 1 (SQSTM1) is a multifunctional protein that plays a central role in protein homeostasis and stress responses by regulating autophagy and signal transduction pathways. Through its multiple protein-interacting domains, p62 functions both as a scaffold for selective autophagic degradation and as a signaling hub. Since our previous review of p62 a decade ago, substantial progress has been made in elucidating its molecular functions and physiological roles. Notably, p62 undergoes liquid-liquid phase separation with ubiquitinated proteins to form membraneless condensates, termed p62 bodies, when cells are exposed to proteotoxic stress. By sequestering specific proteins, p62 bodies act as platforms for autophagy-dependent degradation and stress signaling. These findings have substantially revised our view of p62 function, which was previously considered primarily as a receptor simply linking ubiquitinated substrates to autophagic membranes and connecting signaling molecules. This conceptual shift from one-to-one molecular interactions to multivalent, multimolecular, higher-order assemblies has fundamentally redefined the functional landscape of p62. In this review, we highlight how p62 bodies integrate selective autophagy and stress signaling, with a particular emphasis on their emerging roles in disease pathogenesis and their potential as therapeutic targets.

Keywords:  KEAP1‐NRF2 pathway; liquid–liquid phase separation; p62 body; p62/SQSTM1; selective autophagy; ubiquitination

DOI:  https://doi.org/10.1111/febs.70689
Nat Cardiovasc Res. 2026 Aug;5(8): 675-692

Established and emerging roles of lysosomal dysfunction in cardiac aging.

Yohan Santin, Ilias Simon, Angelo Parini, Frank Lezoualc'h, Elena Sommariva.

Cardiac aging is a central biological process underlying most cardiovascular diseases. Lysosomes, once regarded as terminal degradative compartments, are now recognized as dynamic metabolic and signaling hubs whose dysfunction has profound consequences for the aging heart. Human lysosomal storage disorders provide compelling evidence that isolated lysosomal defects are sufficient to cause early cardiomyopathy, underscoring the myocardium's exceptional dependence on sustained lysosomal competence. In physiological aging, impaired autophagy is the most apparent manifestation of lysosomal decline but represents only one facet of a broader network regulating nutrient sensing, ion and lipid homeostasis, receptor trafficking, exocytosis/secretion and inter-organelle communication. Here, we review established and emerging lysosome-dependent mechanisms across the hallmarks of cardiac aging, highlighting lysosomes as potential upstream drivers of this process. We discuss key knowledge gaps and therapeutic strategies aimed at restoring lysosomal function, positioning lysosomes as central and actionable targets for preserving cardiac resilience with age.

DOI: https://doi.org/10.1038/s44161-026-00853-z
Nat Rev Mol Cell Biol. 2026 Aug 14.

Regulation and roles of mammalian mitophagy.

Sascha Martens, Ian G Ganley.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.

DOI: https://doi.org/10.1038/s41580-026-01012-9
Autophagy Rep. 2026 ;5(1): 2705631

FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.

Halvor Ullern, Julie Aarmo Johannessen, Feyza Kasikci, Miriam Formica, Naghmeh Karimi Melve, Siri Andresen, Andreas Brech, Karol Axcrona, Kjersti Jørgensen, Lorant Farkas, Jorrit M Enserink, Helene Knævelsrud.

  Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation were unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate aberrant p62 accumulation in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate that FLCN loss is characterized by SQSTM1/p62 accumulation, although SQSTM1/p62 appears dispensable for anchorage-independent growth in cell models.

Keywords:  Autophagy; BHD; FLCN; SQSTM1/p62; renal cell carcinoma

DOI:  https://doi.org/10.1080/27694127.2026.2705631
Int J Mol Sci. 2026 Jul 26. pii: 6670. [Epub ahead of print]27(15):

Autophagy in Melanoma: Molecular Mechanisms and Therapeutic Perspectives.

Dominika Stencel, Dorota Wrześniok.

  Melanoma is a malignant tumor that originates in pigment-producing cells called melanocytes. This type of cancer remains a major public health challenge due to its high metastatic potential and resistance to treatment. Autophagy is a catabolic process that enables the controlled degradation of damaged cellular organelles and unnecessary or abnormal macromolecules. Its primary function is to maintain intracellular homeostasis and cell survival. There are three main types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The role of autophagy in oncogenesis is multifaceted and context-dependent-depending on the type of cancer and its stage of development. Autophagy can either promote tumor progression or act as a tumor-suppressive mechanism. Factors influencing the role of autophagy in cancer include inflammation, crosstalk with apoptosis and resistance to anticancer therapies. Current research is focused on the use of both autophagy inhibitors and autophagy inducers as potential strategies to improve the effectiveness of melanoma treatment.

Keywords:  autophagy; cancer; melanoma; oncogenesis

DOI:  https://doi.org/10.3390/ijms27156670
Bone Rep. 2026 Sep;30 101941

Autophagy in Osx1-Cre-targeted cells is essential for development, growth, and maintenance of bone.

Alicen James, Ilham Kadhim, Jacob Laster, Vivek Khanal, Jeff Thostenson, Neha Dole, Jinhu Xiong, Intawat Nookaew, Melda Onal.

  Autophagy is a cellular recycling pathway in which cytoplasmic components are delivered to lysosomes for degradation. Changes in autophagy levels have been implicated in various skeletal pathologies including osteoporosis. Elimination of autophagy at different stages of the osteoblast lineage reduces bone formation and bone mass. However, whether autophagy plays a role specifically during development, growth, or maintenance of bone remains unclear. To start addressing this question, we eliminated autophagy in the entire osteoblast lineage prenatally or at weaning and subjected the mice to skeletal phenotyping at 4.5 and 10 months of age. We found that regardless of when autophagy was eliminated from the osteoblast lineage, autophagy deficiency reduced bone mineral density (BMD), cortical thickness, and cancellous bone volume in the femur and spine. Serial BMD analysis revealed that autophagy-deficient mice had consistently lower BMDs from 3 to 9 months of age, and the BMD difference between genotypes became progressively greater in the spine. The reduction in vertebral cancellous bone volume of autophagy-deficient mice was associated with reduced bone formation. To assess autophagy-induced changes at the cellular and molecular level, we performed single-cell RNA-sequencing (scRNA-seq) analysis of periosteal mesenchymal cells and compared autophagy deficiency-induced changes in periosteal and endosteal cell preparations. This analysis revealed that autophagy deficiency disrupts proteostasis, causes mitochondrial dysfunction, induces senescence, and increases stress response pathways like TNF and TGF-β. Overall, we conclude that autophagy is important for skeletal growth and maintenance of bone, and we identify potential cellular populations and cellular processes via which autophagy support bone formation.

Keywords:  Autophagy; Bone biology; Cell biology; Osteoblasts

DOI:  https://doi.org/10.1016/j.bonr.2026.101941
FEBS J. 2026 Aug 14.

A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.

Fangze Tong, Mateo P Hoare, Laura J Grundy, Filomena Gallo, Karin H Müller, Ewan St John Smith, Janet R Kumita.

  Naked mole-rats (NMRs, Heterocephalus glaber) display unusual longevity and resistance to age-related decline, and accumulating evidence suggests that their autophagy-lysosome pathway (ALP) is regulated differently from that of conventional mammalian models. However, most studies in NMR cells have relied on static biochemical or ultrastructural readouts, leaving the dynamic organisation of autophagy in living cells poorly defined. Here, we establish a stable tandem fluorescent autophagy reporter in NMR skin fibroblasts using an mCherry-EGFP-LC3NMR construct to enable live-cell, single-cell resolution analysis of ALP dynamics. Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP. Chloroquine (CQ)-induced lysosomal stress caused the expected accumulation of LC3-positive structures but also triggered the formation of large cytoplasmic vacuoles in NMR skin fibroblasts. Importantly, this vacuolation was not associated with acute cytotoxicity and progressively resolved following CQ removal, accompanied by reorganisation of LC3-positive compartments and recovery of lysosomal acidity. Electron microscopy showed that CQ-induced vacuoles are membrane-bound, containing internal material and co-existing with multiple ALP-related vesicular compartments. Primary NMR skin fibroblasts display a similar vacuolation phenotype, indicating that this response is not an artefact of immortalisation or reporter expression. Together, these findings establish a live-cell platform for analysing autophagy in NMR cells and identify a distinctive, reversible vacuolation response to lysosomal stress, consistent with dynamic remodelling of the lysosomal system within NMR skin fibroblasts.

Keywords:  LC3‐reporter; autophagy–lysosome pathway; long‐lived species; naked mole‐rats; vacuolation

DOI:  https://doi.org/10.1111/febs.70695
Traffic. 2026 Sep;27(3): e70045

Mechanism of Autophagic Extracellular Vesicles Revealed.

Constantinos Demetriades, Thierry Galli.

Recent work by Mao and colleagues identifies a distinct class of small extracellular vesicles, termed autophagic extracellular vesicles (AEVs), generated from amphisomes upon autophagy induction. In this commentary, we discuss how this study provides important mechanistic insight into the coupling between autophagy and secretion. AEVs are molecularly and functionally distinct from canonical exosomes, being enriched in autophagy-related components such as LC3 and p62, and dependent on core ATG machinery for their biogenesis. Notably, their secretion is enhanced by autophagy induction and contributes to intercellular communication, particularly in the context of viral infection. These findings position amphisomes as critical sorting hubs that direct cargo toward either degradation or secretion, thereby integrating autophagic and endolysosomal pathways. We further highlight how these results intersect with prior evidence implicating SNARE-dependent mechanisms, including VAMP7 and stress-responsive regulators such as GRASP55, in unconventional secretion. Finally, we discuss key unresolved questions, particularly the mechanisms underlying the generation of small intraluminal vesicles within amphisomes and the role of ESCRT machinery in this process. Overall, the identification of AEVs adds a new layer of complexity to extracellular vesicle biology and opens new avenues for understanding how autophagy contributes to intercellular signaling in health and disease.

DOI: https://doi.org/10.1111/tra.70045
J Physiol Biochem. 2026 Aug 12. pii: 78. [Epub ahead of print]82(1):

AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.

Wenjing Song, Zhifei Ke.

  Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that links cellular energy stress with metabolic adaptation, autophagy, redox homeostasis, and cell fate decisions. Necroptosis is a regulated lytic form of cell death driven by receptor-interacting serine/threonine kinases 1 and 3 (RIPK1 and RIPK3), with mixed lineage kinase domain-like protein (MLKL) serving as the terminal executor. Increasing evidence suggests that AMPK modulates necroptosis through multiple interconnected mechanisms. AMPK directly phosphorylates RIPK1, thereby influencing necroptotic signaling in a context- and time-dependent manner. Through the AMPK-mTOR axis, AMPK also regulates autophagy and mitophagy, affecting inhibitory control of RIPK1 and autophagic turnover of RIPK3. In parallel, AMPK suppresses necroptosis through SIRT1- and PGAM5-related pathways, limiting necrosome assembly, mitochondrial dysfunction, and Drp1-dependent mitochondrial fission. AMPK further shapes reactive oxygen species (ROS)-associated necroptotic responses through downstream effectors, including mTOR and Nrf2. In this review, we summarize recent advances in the mechanisms by which AMPK regulates necroptosis and highlight unresolved questions, including the cell-type-specific roles of AMPK subunits, the contribution of additional autophagy regulators, the balance between mTORC1-dependent protective signaling and RIPK3 stability, and the in vivo relevance of the AMPK-SIRT1-PGAM5 axis. Clarifying this regulatory network may facilitate the development of therapeutic strategies for necroptosis-related diseases, including metabolic disorders, ischemia-reperfusion injury, and neurodegeneration. Collectively, the available evidence indicates that AMPK acts as a context-dependent regulator of necroptosis rather than a universally protective kinase.

Keywords:  AMPK; Autophagy; Mitochondrial fission; Mitophagy; Necroptosis; Oxidative stress

DOI:  https://doi.org/10.1007/s13105-026-01221-y
Autophagy. 2026 Aug 12. 1-3

New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.

Sabrina Chumpen Ramirez, Dmitry Shvarev, Fulvio Reggiori, Christian Ungermann.

  Atg9-Atg2-Atg18 complexes are essential for the biogenesis of the autophagosome as they mediate the elongation of the phagophore, the precursor structure of autophagosomes. This event occurs by the transfer of lipids through a membrane contact site (MCS) between the phagophore and the endoplasmic reticulum exit sites (ERES). The bridge-like lipid-transfer protein (BLTP) Atg2 interacts with the Atg9 and phosphatidylinositol-3-phosphate (PtdIns3P) on the phagophore and acts as a tether to establish this MCS. While not essential to form the phagophore-ERES MCS, Atg18 plays a crucial role in the phagophore elongation by stimulating Atg2 lipid transfer activity, based on in vitro experiments. To understand the molecular basis of this regulation, we recently solved the structure of the yeast Atg2-Atg18 complex using cryo-electron microscopy (cryo-EM) and identified the critical region in Atg2 required for the Atg2-Atg18 complex formation. Importantly, we applied structure-function analyses to unveil the molecular mechanism behind the Atg18-mediated stimulation of Atg2. We showed that Atg18 binding to Atg2 induces a structural repositioning of the hydrophobic cavity of Atg2 toward the membrane, which allows efficient transfer of lipids from the endoplasmic reticulum to the phagophore. Here, we summarize our recent work and extend our discussion on the molecular regulation of the lipid transfer activity, highlighting open questions concerning the function of the Atg9-Atg2-Atg18 module in the phagophore-ERES MCS.Abbreviations: ATG, autophagy related; BLTP, bridge-like lipid-transfer protein; cryo-EM, cryo-electron microscopy; ER, endoplasmic reticulum; ERES, ER exit sites; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; TRAPPIII, transport protein particle III.

Keywords:  Atg18; Atg2; Atg9; autophagy; lipid transfer; phosphatidylinositol-3-phosphate

DOI:  https://doi.org/10.1080/15548627.2026.2716596
Front Neurosci. 2026 ;20 1885103

Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.

Jiaojiao Fu, Chuanxi Zhu, Zhenzhen Fan.

  Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized pathologically by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, which predominantly consist of misfolded α-synuclein (α-Syn) aggregates. Recent advances have highlighted the critical role of the interplay between α-Syn and lysosomal function, termed the α-Syn-lysosome axis, as a central mechanism underlying PD pathogenesis. This review systematically summarizes the molecular mechanisms driving α-Syn aggregation and the lysosomal dysfunction contributing to impaired autophagy-lysosome pathway (ALP) activity. We further discuss emerging therapeutic strategies targeting this axis to restore lysosomal function and mitigate α-Syn toxicity. By integrating the latest findings from molecular biology, cell biology, and preclinical studies, this article aims to elucidate the complex regulatory network of the α-Syn-lysosome axis and provide a theoretical foundation for the development of novel therapeutic interventions for PD.

Keywords:  Parkinson’ s disease; autophagy; lysosome; protein aggregation; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2026.1885103
FEBS Lett. 2026 Aug 10.

Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.

Rainer Ettelt, Ana-Maria Sandru, Georg Vucak, Sebastian Didusch, Biljana Riemelmoser, Karin Ehrenreiter, Markus Hartl, Lukas A Huber, Manuela Baccarini.

  Lysosomes are dynamic organelles regulating metabolic signaling by recruiting cytosolic molecules to protein platforms on their limiting membrane. We used proximity labeling to define interactors and vicinal proteins of LAMTOR3, a component of the Ragulator scaffold that controls mTORC1 signaling and lysosome positioning. The screen has yielded several previously unappreciated interactors, including an actin remodeling network. Here, we characterize the RhoGEF PLEKHG3 as a LAMTOR3 vicinal protein colocalizing with peripheral lysosomes and cortical F-actin at focal adhesion sites. Forced peripheral dispersion of lysosomes drives PLEKHG3 accumulation at focal adhesions and decreases protrusive activity in both wild-type and PLEKHG3-deficient cells. Thus, lysosome positioning governs both PLEKHG3 localization and protrusive activity, yet the protrusion changes can occur independently of PLEKHG3.

Keywords:  LAMTOR; PLEKHG3; cell motility; cytoskeleton; focal adhesions; lysosomes

DOI:  https://doi.org/10.1002/1873-3468.70428
Cells. 2026 Jul 28. pii: 1361. [Epub ahead of print]15(15):

TRPM2 Promotes Lipophagy Through TFEB and LAL in HFD-Fed Mice.

Fan Ying, Duan Zhuo, Shaobo Zhou, Liwen Jiang, Xiaoqiang Yao.

  An abnormality of Ca2+ signaling may aggravate lipid accumulation in steatotic hepatocytes, leading to non-alcoholic fatty liver disease. However, the molecular identity of Ca2+-permeable channels and the mechanism of involvement of these channels in steatotic hepatocytes are not well-studied. In the present study, we investigated the role of a Ca2+-permeable channel TRPM2 in lipid metabolism in steatotic hepatocytes. A mouse model of non-alcoholic fatty liver disease was established by high-fat-diet feeding. Fat accumulation, fibrosis, lipophagic indexes, TFEB and lysosomal acid lipase in the liver tissue and/or hepatocytes were compared between TRPM2-knockout mice and wild-type mice. Knockout of the TRPM2 gene aggravated liver fat accumulation and fibrosis. Mechanistically, the TRPM2 knockout impaired the lipophagic process, decreased lysosomal abundance and attenuated lysosomal/autolysosomal acidification in mouse hepatocytes. Furthermore, the TRPM2 knockout reduced TFEB expression and its nuclear translation and also reduced the expression/activity of lysosomal acid lipase. These data demonstrate that TRPM2 deficiency may reduce lipophagy via its action on TFEB and lysosomal acid lipase, consequently contributing to liver steatosis and NAFLD under high-fat feeding conditions.

Keywords:  TRPM2 channels; lipophagy; lysosomal acid lipase; lysosomal biogenesis

DOI:  https://doi.org/10.3390/cells15151361
Cells. 2026 Aug 04. pii: 1411. [Epub ahead of print]15(15):

Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias.

Silvia Tortoriello, Simona Rossi, Ilaria Della Valle, Nadia D'Ambrosi, Mauro Cozzolino.

  Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in polyglutamine (polyQ) cerebellar ataxias, or to RNA-mediated toxicity and repeat-associated non-AUG (RAN) translation, for which recent evidence supports a major pathogenic role in non-coding spinocerebellar ataxias (SCAs). Despite these distinct upstream mechanisms, disruption of neuronal homeostasis occurs through converging pathogenic processes, including proteostasis impairment, transcriptional dysregulation, and mitochondrial dysfunction, leading to progressive neuronal loss. Importantly, impaired autophagy has been consistently reported across multiple repeat expansion ataxias, including both dominant SCAs and recessive conditions, such as Friedreich's ataxia, suggesting that impairment of this pathway may represent a shared downstream event in disease progression. Indeed, in polyQ cerebella ataxias, the accumulation of misfolded and aggregation-prone proteins places a substantial burden on cellular quality control systems, particularly the ubiquitin-proteasome system and autophagy. Similarly, in non-coding SCAs, toxic RNA species and RAN-derived peptides might interfere with protein clearance mechanisms and contribute to cellular stress. In this review, we will discuss the evidence supporting autophagy impairment as a convergent pathogenic pathway in repeat expansion cerebellar ataxias.

Keywords:  RAN translation; RNA toxicity; autophagy; repeat expansion disorders; spinocerebellar ataxia

DOI:  https://doi.org/10.3390/cells15151411
Autophagy. 2026 Aug 11. 1-21

Senecavirus a 3C protease cleaves RETREG1 to antagonize ER-phagy and promote viral replication via endoplasmic reticulum calcium signaling.

Jingyu Mao, Ju Yu, Penghui Zeng, Xiaoyu Yang, Yongyan Shi, Yunjie Qu, Jianwei Zhou, Dedong Wang, Jiangwei Song, Yong Wang, Jue Liu, Lei Hou.

  Co-evolution between viruses and autophagy has led to the emergence of viral strategies that manipulate host endoplasmic reticulum (ER) homeostasis, ultimately promoting viral replication. ER turnover is achieved through selective autophagy, also referred to as ER-phagy, which is regulated by the RETREG1/FAM134B (reticulophagy regulator 1) family of reticulon proteins. Nevertheless, how viruses target RETREG1, a receptor for ER-phagy, remains largely unclear. In this study, we demonstrate that infection with Senecavirus A (SVA), an emerging picornavirus, triggers the cleavage of RETREG1, which functions as a negative regulator of viral replication. By screening viral proteins, we identified the SVA 3C protease (3C[pro]) as the executor of this cleavage event. Detailed mapping revealed that residues Q428, E430, and G431 of RETREG1 are involved in its cleavage by the 3C[pro], and the resulting two fragments fail to suppress viral replication. Furthermore, proteolytic cleavage of RETREG1 by 3C[pro] impairs its ability to relieve ER stress and mediate ITPR1 degradation via RETREG1-dependent ER-phagy. This disruption leads to increased ER calcium (Ca2+) release and subsequent activation of autophagy through the CAMKK2-PRKAA2-MTOR axis, which ultimately facilitates SVA replication. Taken together, these findings indicate that SVA antagonizes the antiviral function of RETREG1-mediated ER-phagy via its 3C[pro], highlighting RETREG1 as a potential therapeutic target for combating SVA infection.Abbreviations: 2-APB: 2-aminoethyl diphenylborinate; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; ATL3: atlastin GTPase 3; BHK-21: baby hamster kidney-21; CAMKK2: calcium/calmodulin dependent proteinkinase kinase2; CCPG1: cell cycle progression 1; CKAP4/CLIMP63: cytoskeleton associated protein 4; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DM: double mutant; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; eGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; GFP: green fluorescent protein; HSPA5/GRP78/BiP: heat shock protein family A (Hsp70) member 5; HA: hemagglutinin; HDAC4: histone deacetylase 4; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; IFA: indirect immunofluorescence assay; ITPR1/IP3R1: inositol 1,4,5-trisphosphate receptor type 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; mCherry: monomeric cherry; MTOR: mechanistic target of rapamycin kinase; REEP5: receptor accessory protein 5; RETREG1/FAM134B: reticulophagy regulator 1; RTN3: reticulon 3; SD: standard deviation; SEC61B: SEC61 translocon subunit beta; SEC62: SEC62 preprotein translocation factor; SERP1/RAMP4: stress associated endoplasmic reticulum protein 1; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; ST: swine testis; SVA: Senecavirus A; TEM: transmission electron microscopy; TEX264: testis expressed 264, ER-phagy receptor; Tm: tunicamycin; U2OS: human osteosarcoma epithelial cells; UV: ultraviolet; ZVAD-FMK: benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone; μg: microgram; μm: micrometer; μM: micromole.

Keywords:  CAMKK2-PRKAA2-MTOR axis; Calcium (Ca2+); ER-phagy; RETREG1 cleavage; SVA 3C[pro]; viral replication

DOI:  https://doi.org/10.1080/15548627.2026.2714544
Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00910-1. [Epub ahead of print]45(8): 117832

ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.

Matthew D Demmings, Erica A Kane, Elizabeth C Tennyson, Kate Hurley, Joy Zhao, Nicholas A Cruickshanks, Victoria Ciz, Jordan M Krupa, Stephen H Pasternak, Sean P Cregan.

  The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and α synucleinopathy models of PD in vitro and in vivo. We show that sustained activation of ATF4, the central ISR transcription factor, induces the coordinated transcriptional upregulation of SESN2, DDIT4, and Trib3, which cooperate to suppress both mTORC1 and mTORC2 activity. This ATF4-dependent inhibition of mTOR signaling promotes dopaminergic neuron death by facilitating activation of the pro apoptotic BCL 2 family protein PUMA. Together, these findings define a maladaptive ISR/ATF4-mTOR pathway with potential therapeutic relevance for neurodegenerative disorders characterized by chronic ISR activation.

Keywords:  ATF4; CP: molecular biology; CP: neuroscience; ISR; PUMA; dopaminergic neurons; integrated stress response; mTOR; neurodegeneration; α-synuclein

DOI:  https://doi.org/10.1016/j.celrep.2026.117832
Sci Adv. 2026 Aug 14. 12(33): eaee0509

Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

Wenhao Zhao, Xudong Hu, Ruyi Wang, Han Zhang, Man Zhou, Hong Cao.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the NPC1 gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an npc1-knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that npc1 deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.

DOI: https://doi.org/10.1126/sciadv.aee0509
Biology (Basel). 2026 Jul 27. pii: 1240. [Epub ahead of print]15(15):

Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.

Huiying Zhao, Min Chen.

  Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies.

Keywords:  exercise; mitochondria; mitochondrial quality control; skeletal muscle

DOI:  https://doi.org/10.3390/biology15151240
Front Neurol. 2026 ;17 1924943

α-Synuclein burden amplification in Parkinson's disease: a unified genetic, molecular, and cellular framework.

Sachiko Noda, Nobutaka Hattori.

   Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the accumulation and propagation of α-synuclein (α-syn). Although α-syn aggregation is considered central to PD pathogenesis, increasing evidence suggests that α-syn abundance may be as important as its conformational state. Genetic studies have demonstrated an SNCA dosage effect, with gene duplication and triplication associated with progressively more severe familial PD phenotypes. Complementary evidence indicates that dysfunction of protein clearance pathways, particularly the autophagy-lysosome system, promotes intracellular α-syn accumulation and increases its neurotoxic potential. In this review, we propose α-syn multiplication as an integrative framework for interpreting PD pathogenesis. This concept extends beyond SNCA copy-number variation to encompass processes that increase the effective α-syn burden within neurons or across neural networks, including increased gene expression, impaired degradation, disrupted proteostasis, and pathological propagation.
Methods: We summarize α-syn structural dynamics and the concentration-dependent distribution of monomeric, oligomeric, and fibrillar species. We then review evidence from SNCA gene-dosage studies and examine the role of the autophagy-lysosome pathway in regulating α-syn homeostasis, with particular emphasis on recent experimental findings demonstrating that autophagy deficiency exacerbates α-syn accumulation and neurodegeneration in human α-syn bacterial artificial chromosome transgenic mice.
Results: Collectively, the available genetic, biochemical, and experimental evidence supports a model in which the balance between α-syn production and clearance influences disease progression alongside protein misfolding. The interaction between increased protein burden and impaired clearance capacity provides a unifying mechanism linking familial and sporadic forms of PD.
Discussion: We propose that α-syn multiplication offers an integrative framework for understanding PD pathogenesis, provides a quantitative perspective on disease heterogeneity, and highlights therapeutic opportunities aimed at reducing α-syn burden and restoring proteostatic balance.

Keywords:  Parkinson’s disease; SNCA; autophagy–α-synuclein homeostasis; neurodegeneration; protein aggregation; α-synuclein

DOI:  https://doi.org/10.3389/fneur.2026.1924943
Sci Adv. 2026 Aug 14. 12(33): eaeh0657

Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.

Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.

Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.

DOI: https://doi.org/10.1126/sciadv.aeh0657
Mol Cell Neurosci. 2026 Aug 08. pii: S1044-7431(26)00042-4. [Epub ahead of print]138 104112

The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.

Mustafa M Shokr, Mohamed N Fawzy.

  Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.

Keywords:  AMPK/SIRT1 signaling; Gut–brain axis; Mitophagy; PGC-1α activation; Urolithin A

DOI:  https://doi.org/10.1016/j.mcn.2026.104112
Antioxid Redox Signal. 2026 Aug 09. 15230864261470736

Dual Regulation of ACSL3 by TRIM33-Mediated Ubiquitination and NBR1-Dependent Autophagy: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.

Yueqing Yang, Ming Zhao, Yibo Feng, Hongli Yu, Yuanxin Gong, Qingqing Liu.

   BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a key contributor to stroke-related neurological damage, but the functional interplay between autophagy and ferroptosis-two critical pathological processes-remains poorly understood.
METHODS: Using oxygen-glucose deprivation/reperfusion in PC12 cells and middle cerebral artery occlusion (MCAO) in rats, we combined molecular, pharmacological, and imaging approaches to investigate how autophagy regulates the ferroptosis suppressor acyl-CoA synthetase long-chain family member 3 (ACSL3).
RESULTS: Ischemia-reperfusion triggered hyperactivated autophagy, which promoted ferroptosis by selectively targeting ACSL3 for degradation via the autophagy receptor neighbor of BRCA1 gene 1 protein (NBR1). We further identified that tripartite motif-containing protein 33 (TRIM33), an E3 ubiquitin ligase induced after ischemia, directly ubiquitinates ACSL3 and facilitates its proteasomal degradation. This ubiquitin-mediated pathway acted synergistically with autophagy to control ACSL3 stability. Pharmacological inhibition of autophagy with curcumin derivative 5g (CUR5g) restored ACSL3 protein levels and suppressed ferroptosis. In MCAO rats, CUR5g-administered alone or in combination with the ferroptosis inhibitor Ferfluor-1-significantly improved functional recovery and reduced brain injury.
CONCLUSION: Our study reveals a novel autophagy-NBR1/TRIM33-ACSL3 regulatory axis that drives ferroptosis in CIRI, highlighting a promising therapeutic strategy for ischemic stroke through cotargeting autophagy and ferroptosis. Antioxid. Redox Signal. 00, 000-000.

Keywords:  ACSL3; NBR1; TRIM33; autophagy; cerebral ischemia-reperfusion injury (CIRI); ferroptosis

DOI:  https://doi.org/10.1177/15230864261470736
Nutrients. 2026 Aug 03. pii: 2511. [Epub ahead of print]18(15):

Natural Bioactive Compounds Targeting Key Hallmarks of Aging: Functional Food Potential of Spermidine, Fisetin, Berberine, and Urolithin A.

Wojciech Rzeski, Weronika Rzeska.

  Naturally derived bioactive compounds that modulate aging-associated mechanisms have attracted growing research interest, yet few reviews examine how such compounds might act together. This narrative review examines four mechanistically distinct compounds, namely spermidine, fisetin, berberine, and urolithin A, as emerging functional food ingredients with scientifically supported effects on key hallmarks of human aging. Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. Fisetin, a flavonoid from strawberries and apples, exerts senolytic activity by selectively eliminating senescent cells via PI3K/AKT and Bcl-2/Bcl-xL inhibition, with emerging clinical evidence. Berberine, an isoquinoline alkaloid from Berberis species, modulates metabolic dysfunction via AMP-activated protein kinase (AMPK) activation and reshapes gut microbiota composition through direct high intraluminal exposure, with the most extensive clinical dataset of the four compounds. Urolithin A, a gut microbiome-derived postbiotic from ellagitannins in pomegranates and nuts, induces mitophagy via PINK1/Parkin and has been evaluated in a growing number of registered human clinical trials. Together, the four compounds primarily target distinct but complementary aging-associated pathways (autophagy, senolysis, metabolic regulation, mitophagy), suggesting rational potential for combined functional food formulations. Limited direct evidence for their combined use and the need for dedicated co-administration studies are discussed, alongside bioavailability, safety, and regulatory considerations.

Keywords:  aging; autophagy; berberine; bioactive compounds; fisetin; functional food; healthspan; mitophagy; senolysis; spermidine; urolithin A

DOI:  https://doi.org/10.3390/nu18152511
Life Sci Space Res (Amst). 2026 Sep;pii: S2214-5524(26)00049-0. [Epub ahead of print]52 222-236

Simulated microgravity induces a time-dependent shift from autophagy to apoptosis in osteoblasts, validated by TSPO, ATG12, and BNIP3L expression in vivo.

Ao Yang, Bo Peng, Fei Teng, Yi Chen, Shifeng Zhang, Fei Yang, Yayi Xia, Bin Geng.

  Emerging evidence indicates that microgravity-induced osteoblast dysfunction is a critical contributor to spaceflight-associated bone loss. This study investigated the temporal dynamics of autophagy-apoptosis crosstalk in MC3T3-E1 osteoblasts under a rotary cell culture system (RCCS)-simulated microgravity. Crucially, time-course analysis (1, 3, 5, 10 days) revealed a biphasic autophagic response: initial enhancement of autophagic flux (LC3-II/Beclin-1 upregulation, p62 degradation) at day 3, exerting cytoprotective effects with reduced apoptosis, subsequently shifting to peak autophagy inhibition at day 5 concomitant with marked apoptosis activation (cleaved caspase-3 elevation) and mitochondrial dysfunction. By day 10, extensive cellular fragmentation dominated. Integrated proteomics identified TSPO, ATG12, and BNip3L as important mediators of this phenotypic switch. Murine hindlimb unloading experiments validated the upregulation of these proteins in bone tissue via Western blot and immunohistochemistry . We hypothesize that Early microgravity exposure triggers compensatory autophagy via ATG12-mediated vesicle expansion, whereas sustained stress is accompanied by TSOPO-associated ROS accumulation and BNip3L-linked alteration in autophagy-related pathways, contributing to apoptosis. Our finding suggests a biphasic temporal pattern in autophagy-apoptosis remodeling under simulated microgravity, highlighting potential time-sensitive windows for future therapeutic targets for spaceflight-associated osteopenia.

Keywords:  Apoptosis; Autophagy; Microgravity; Osteoporosis

DOI:  https://doi.org/10.1016/j.lssr.2026.03.005
Cells. 2026 Jul 26. pii: 1340. [Epub ahead of print]15(15):

The E. coli High-Pathogenicity Island Downregulates PI3K/Akt/mTOR Expression and Induces Autophagy in the Mouse Intestine.

Wen Li, Bo Zhang, Weiwei Zhao, Hao Wang, Meng Zhou, Yue Li, Jinzhi Ma, Leyi Chu, Xiaofeng Ruan, Peng Xiao, Hong Gao.

  The high-pathogenicity island (HPI) is a major virulence determinant in pathogenic Escherichia coli (E. coli), contributing to severe inflammation and tissue damage. Autophagy plays a critical role in clearing intracellular pathogens and modulating inflammation, but whether HPI manipulates this process remains unknown. Here, using a swine-pathogenic E. coli strain and its HPI-deficient mutant (Δirp2) generated by CRISPR/Cas9, we investigated the interplay between HPI and autophagy in RAW264.7 macrophages and a mouse intestinal infection model. We found that HPI+ infection induced autophagic activation, as evidenced by increased LC3 puncta (immunofluorescence), upregulated Beclin-1 and autophagy-related gene mRNA levels (qPCR), and downregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) expression at both mRNA (qPCR) and protein (immunohistochemistry) levels. In a mouse model, HPI+ infection upregulated intestinal Microfold (M) cell markers and secretory Immunoglobulin A (IgA), triggered robust production of pro-inflammatory cytokines, and induced more severe tissue pathology than the HPI-deficient mutant. Pharmacological activation of autophagy with rapamycin alleviated HPI-induced inflammation and injury, whereas inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 silencing exacerbated damage. These findings suggest that HPI induces autophagy, but the endogenous autophagic response is insufficient to counteract HPI-induced pathology; pharmacological enhancement of autophagy partially alleviated this insufficiency and reduced tissue damage. Notably, Beclin-1 knockdown blunted HPI-induced upregulation of PI3K and autophagy-related genes, suggesting a role for Beclin-1 in the transcriptional regulation of these responses. In conclusion, HPI simultaneously exerts direct pro-inflammatory effects and induces Beclin-1-dependent autophagy. Enhancing this autophagic response pharmacologically, rather than relying on the endogenous level triggered by HPI alone, limits excessive tissue damage. Thus, boosting autophagy may represent a promising therapeutic strategy against HPI-bearing pathogenic E. coli infections.

Keywords:  Escherichia coli; PI3K/Akt/mTOR pathway; autophagy; high-pathogenicity island (HPI); macrophages

DOI:  https://doi.org/10.3390/cells15151340
J Mol Biol. 2026 Aug 13. pii: S0022-2836(26)00363-3. [Epub ahead of print] 169990

The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.

Valérie Carraro, Maëlle Cherpaz, Lucie Longechamp, Cécile Coudy-Gandilhon, Laurent Parry, Guillaume Voyard, Anne-Catherine Maurin, Céline Jousse, Julien Averous, Lydie Combaret, Isabelle Papet, Alain Bruhat.

  Mammals rely on the integrated stress response (ISR) to maintain essential amino acid (EAA) homeostasis. The kinase GCN2 is a key ISR sensor that is rapidly activated by uncharged tRNAs during EAA deprivation, leading to eIF2α phosphorylation and selective translation of ATF4. ATF4 subsequently orchestrates a transcriptional program regulating amino acid metabolism, redox balance, and autophagy. In this study, we investigated the role of GCN2 in the early hepatic transcriptional response to dietary sulfur amino acids (SAA; methionine and cysteine) deprivation. Using ATF4-luciferase reporter mice, we demonstrate that short-term SAA deprivation rapidly activates the eIF2α-ATF4 pathway within 3 hours, with activation primarily localized to the liver. Complementary in vivo and ex vivo approaches revealed that genetic deletion or pharmacological inhibition of GCN2 abolishes early eIF2α phosphorylation and induction of ATF4 target gene, while PERK is dispensable for this response. Furthermore, GCN2 controls the induction of multiple adaptive transcriptional programs involved in amino acid transport, aminoacyl-tRNA synthesis, autophagy, serine biosynthesis, one-carbon metabolism and glutathione degradation highlighting a coordinated adaptive response to acute SAA deprivation. These findings establish GCN2 as a major sensor mediating the early hepatic response to SAA deprivation, and define a transcriptional program essential for maintaining amino acid homeostasis. In contrast, Fgf21 induction occurs independently of GCN2, indicating the existence of parallel adaptive mechanisms. Collectively, this work provides new insight into the early dynamics and molecular specificity of ISR activation in response to acute dietary SAA deprivation.

Keywords:  ATF4 signaling; GCN2 kinase; Integrated Stress Response; liver transcriptional response; short-termsulfur amino acid deprivation

DOI:  https://doi.org/10.1016/j.jmb.2026.169990
J Cell Mol Med. 2026 Aug;30(15): e71315

PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.

Yang Yu, Wei Zhang, Yingying Zhao, Yue Zhang, Pingle Li, Zepeng He.

  Post-operative cognitive dysfunction (POCD) is a cognitive disorder characterized by a decline in cognitive function following surgical procedures, with mitophagy identified as a significant underlying mechanism. Protein kinase C delta (PRKCD), localized within the mitochondria, is implicated in the regulation of PINK1/PRKN mitophagy pathway; however, the potential regulatory role of PRKCD in POCD through this pathway remains to be elucidated. Neurons and rats were exposed to sevoflurane (SEV) to illuminate the function and mechanism of PRKCD in POCD. Various methodologies were employed, including immunofluorescence, quantitative real-time PCR, CCK-8 assays, mitochondrial membrane potential (MMP) assessments, MitoSOX generation detection, Seahorse metabolic flux analysis, co-immunoprecipitation, western blotting and behavioural experiments like Morris water maze, novel object recognition and fear conditioning, along with haematoxylin and eosin and immunohistochemical staining. PRKCD was expressed in neurons and that SEV administration led to an upregulation of PRKCD expression. Furthermore, interference with PRKCD was found to restore cell viability in SEV-treated neurons. Additionally, inhibition of PRKCD resulted in the recovery of LC3 expression and the normalization of p62 levels in neurons subjected to SEV treatment. Suppressing PRKCD restored MMP and OCR, reduced MitoSOX in SEV-affected neurons and interacted with PRKN and PINK1, decreasing their expression. Overexpressing PRKN mitigated PRKCD inhibition's impact on mitochondrial damage. In vivo, SEV increased PRKCD, PINK1 and PRKN levels, but PRKCD knockdown improved behavioural and pathological outcomes, reversing changes in LC3-II, PINK1, PRKN and p62 expression. PRKCD enhanced SEV-induced POCD in aged rats via the regulation of PINK1/PRKN mitophagy pathway.

Keywords:  PRKCD; PRKN; mitophagy; post‐operative cognitive dysfunction; sevoflurane

DOI:  https://doi.org/10.1111/jcmm.71315
Elife. 2026 Aug 13. pii: RP105386. [Epub ahead of print]14

Parkinson's disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.

Lorenzo Ghezzi, Sabine Kuenen, Ulrike Pech, Nils Schoovaerts, Ayse Kilic, Suresh Poovathingal, Kristofer Davie, Jochen Lamote, Roman Praschberger, Patrik Verstreken.

  Parkinson's disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG), cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG, in turn, disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

Keywords:  D. melanogaster; Parkinson's disease; Pink1; glial cell; neuron-glia interactions; neuroscience

DOI:  https://doi.org/10.7554/eLife.105386
Redox Biol. 2026 Aug 06. pii: S2213-2317(26)00336-8. [Epub ahead of print]96 104337

Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.

Xiaohan Chen, Shunpeng Xing, Xufeng Cen, Jikai Shen, Jiwei Zhu, Xu Lin, Le Xu, Fengqi Wang, Yanan Tian, Xuan Lai, Yuejia Luo, Hongguang Xia, Jian Hu, Luming Wang.

  Acute lung injury (ALI) is driven by excessive inflammation and mitochondrial dysfunction, but how mitochondrial DNA (mtDNA) release engages inflammatory signaling remains incompletely understood. Here, we demonstrate that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation. Transcriptomic and ultrastructural analyses showed that TJ0113 restored mitophagy and reduced oxidative stress. Single-cell transcriptomic profiling identified ZBP1 as the most prominently induced cytosolic nucleic acid sensor in injured lungs, revealing inflammatory alveolar macrophages as a major ZBP1-enriched population. Mechanistically, cytosolic mtDNA accumulation triggered ZBP1 activation, leading to necroptotic (MLKL) and pyroptotic (GSDMD) signaling. TJ0113 suppressed ZBP1 activation by enhancing mitophagy and reducing mtDNA release, and inhibition of mitophagy abolished its protective effects. Consistently, ZBP1 knockdown recapitulated the anti-inflammatory effects of TJ0113, as evidenced by reduced downstream inflammatory signaling and decreased cytosolic Z-NA puncta, and pharmacological mitochondrial depletion (EB) similarly attenuated the inflammatory phenotype. Our findings identify the mtDNA-ZBP1 axis as a critical link between mitochondrial dysfunction and inflammation in ALI, and position TJ0113 as a promising therapeutic candidate targeting this axis.

Keywords:  Acute lung injury; Alveolar macrophages; Mitochondrial DNA; Mitophagy; ZBP1

DOI:  https://doi.org/10.1016/j.redox.2026.104337
Genes Dev. 2026 Aug 10.

mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.

Wenjun Fan, Hester Liu, Liling Yang, Niladri Sinha, Marco Catipovic, Daoyuan Dong, Hariharan Easawaran, Rachel Green, Marikki Laiho.

  Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. To delineate survival mechanisms that allow cancer cells to adapt to ribosome biogenesis defects, we conducted functional genomics screens during inhibition of RNA polymerase I. We identified that inactivation of mTOR enabled cell survival despite severe translational suppression. This was paradoxical as activation of mTOR is considered oncogenic by boosting ribosome biogenesis and cellular translational programs. We show that mTORC1 inhibition does neither restore rRNA synthesis nor ribosome biogenesis, but redistributes limited ribosomes from highly translated 5'TOP mRNAs to survival-essential transcripts. This mTOR inactivation-mediated prioritization of translational resources represents a minimal requirement for cell survival when translational capacity is compromised, which we term "translational fitness." Our findings redefine the role of mTOR in cell survival and highlight the need for strategic targeting of translation regulation in cancer therapy.

Keywords:  adaptive survival; cancer cell survival; mTORC1 signaling; ribosome biogenesis; therapy resistance; translational control; translational fitness

DOI:  https://doi.org/10.1101/gad.353708.126
Mol Genet Genomics. 2026 Aug 11. pii: 169. [Epub ahead of print]301(1):

ZNF143 suppresses mitophagy to drive MASLD progression by regulating SMURF1/TRPV1 axis.

Mei Long, Kewei Tan, Yujie Dong.

  Metabolically dysfunction-associated steatotic liver disease (MASLD), a globally prevalent metabolic condition, is increasingly linked to impaired mitophagy. However, its regulatory mechanisms in MASLD are not fully elucidated. This study investigated the role of Zinc finger protein 143 (ZNF143) in regulating hepatocyte mitophagy during MASLD development and the mechanisms involved. We employed two complementary MASLD models: (1) C57BL/6J mice fed a high-fat diet (HFD) for 16 weeks and (2) Huh-7 cells exposed to free fatty acid (FFA). Pathological changes were detected by H&E Staining. Cellular lipid deposition and mitochondrial damage were assessed using Oil Red O, JC-1 staining and transmission electron microscope (TEM), respectively. The intermolecular interaction was identified by dual-luciferase reporter assay, ChIP, and Co-IP. ZNF143 was upregulated in MASLD models, and its knockdown mitigated lipid accumulation and liver injury by activating hepatocyte mitophagy. ZNF143 promoted SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) transcription by binding to its promoter region. Moreover, SMURF1 mediated transient receptor potential vanilloid type 1 (TRPV1) ubiquitination and degradation. Finally, knockdown of TRPV1 or overexpression of SMURF1 reversed the promoting effect of ZNF143 knockdown on mitophagy in FFA-treated Huh-7 cells. In short, ZNF143 upregulation exacerbated MASLD progression by mediating TRPV1 ubiquitination and degradation through transcriptionally activating SMURF1.

Keywords:  Metabolically dysfunction-associated steatotic liver disease; Mitophagy; SMURF1; TRPV1; ZNF143

DOI:  https://doi.org/10.1007/s00438-026-02501-4