bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–05–24
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. PQ-loop repeat-containing 2 (PQLC2) regulates mTORC1 lysosomal localization and autophagic flux.
  2. Autophagy modulation in cancer.
  3. High-fat diet exacerbates experimental colitis by inhibiting lysosomal function via the STAT3-TFEB Axis.
  4. Identification of a conserved receptor for degrading ribosomes through autophagy.
  5. FGF21 rejuvenates aged human adipose-derived mesenchymal stem cells via enhancement of TFE3-mediated autophagy flux.
  6. The phosphoproteomic landscape of the neurological manifestations in tuberous sclerosis complex.
  7. Chaperone-mediated autophagy is required for regulatory T cell function.
  8. Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis.
  9. Methionine Restriction Extends Yeast Lifespan by Activating Non-Nitrogen-Starvation-Induced Autophagy Through Limiting Methylation of Protein Phosphatase 2A.
  10. Byakangelicin alleviates metabolic dysfunction-associated steatohepatitis by selective inhibition of non-canonical MTORC1 signaling pathway.
  11. A fetus with severe developmental defects caused by dominant-negative and hypomorphic ATG7 alleles.
  12. E2F-mediated activation of mTORC1 through the ubiquitin-proteasome system promotes lung adenocarcinoma progression.
  13. Iterative design leads to a smart probe capable of quantifying autophagic flux with switchable fluorescence via engaging MAP1LC3/LC3.
  14. Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
  15. Mechanisms of TRIM21-mediated RUNX2 degradation via chaperone-mediated autophagy in periodontitis.
  16. mTORC1-signaling switches megalin function from endocytosis to cell cycle progression.
  17. Feedback loops between DNMT1 and autophagy as well as senescence promotes organ aging and canities.
  18. LAPTM5 Promotes Age-Related Renal Fibrosis via USP10/PTEN-Mediated Autophagy Inhibition.
  19. Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.
  20. Real-time in vivo analysis of murine β cells reveals autophagic flux defects before onset of autoimmune diabetes.
  21. Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.
  22. An aging hallmark, Alzheimer's disease, and APOE nexus.
  23. Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
  24. Spatiotemporal dynamics of mTORC1 and mTORC2 in the developing spinal cord and their essential roles in gliogenesis.
  25. Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion.
  26. Elucidating the molecular interplay between LRRK2 and Rab GTPases.
  27. FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration.
  28. Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.
  29. A Rosella-PLIN2 knock-in mouse reveals lipophagy and immunometabolic interplay in atherosclerosis.
  30. Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
  31. Cytosolic DNA as an inhibitor of rDNA transcription.
  32. LPLAT7 Reutilizes Unsaturated 1-Lysophospholipids Formed During Lysosomal Phospholipid Degradation.
  33. Mitophagy in cardiovascular diseases: a literature review.
  34. Thr308-dephosphorylated AKT1 licenses SQSTM1-LC3C-Mediated antiviral autophagy.
  35. Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.
  36. Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.
  37. PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage.
  38. Deficiency of LAMP2A in macrophages accelerates hypoxia-induced atherosclerosis by inhibiting BNIP3-mediated mitophagy.
  39. VCP modulation ameliorates pathological features in C9orf72 models.
  40. Unexpected ribosome turnover during prolonged translation inhibition.
  41. Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.
  42. Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.
  43. Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.
  1. Eur J Cell Biol. 2026 May 19. pii: S0171-9335(26)00015-4. [Epub ahead of print]105(3): 151544
    PQ-loop repeat-containing 2 (PQLC2) regulates mTORC1 lysosomal localization and autophagic flux.
    Yun-Ji Jeung, Minsu Jang, Jiwon Ahn, Ok-Seon Kwon, Seung-Hyun Kim, Jae-Eun Kwon, Yunho Park, Seung Pil Jang, Kajung Ryu, Kyung-Sook Chung.
      PQ-loop repeat-containing 2 (PQLC2) is a lysosomal transporter for cationic amino acid that plays a critical role in regulating intracellular amino acid levels. However, its role in lysosomal biogenesis and autophagy remains poorly understood. Here, we investigate the impact of PQLC2 loss on lysosomal function and autophagic flux using PQLC2 knockdown and knockout cell models. PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes. In addition, genes related to mechanistic target of rapamycin complex 1 (mTORC1), a negative regulator of TFEB, were destabilized, leading to reduced lysosomal recruitment and impaired mTORC1 signaling. Loss of PQLC2 also resulted in lysosomal dysfunction, including defective lysosomal acidification, decreased cathepsin activity, and lysosomal enlargement. Furthermore, autophagosome maturation and autophagic flux were disrupted in PQLC2-deficient cells, as evidenced by p62 accumulation and decreased LC3-II levels. Collectively, our results highlight that PQLC2 is essential for regulating mTORC1-dependent lysosomal function and autophagy, underscoring its potential role in maintaining cellular homeostasis.
    Keywords:  Cathepsins; Lysosomal dysfunction; MTOR localization; MTORC1 stability; PQLC2
    DOI:  https://doi.org/10.1016/j.ejcb.2026.151544
  2. Nat Rev Drug Discov. 2026 May 18.
    Autophagy modulation in cancer.
    Emma Guilbaud, Kevin M Ryan, Douglas R Green, Lorenzo Galluzzi.
      Autophagy is a highly conserved, finely regulated and lysosome-dependent biological process through which eukaryotic cells mobilize metabolites in response to nutrient deprivation and dispose of supernumerary or toxic cytoplasmic entities to ensure cellular quality control. In line with the notion that autophagy globally preserves cellular homeostasis, defects in the molecular machinery for autophagy generally favour malignant transformation. Conversely, proficient autophagic responses are often beneficial to developing tumours as they support the survival of malignant cells facing harsh microenvironmental conditions. Finally, the ability of neoplastic cells to undergo autophagy influences their susceptibility to anticancer immune responses in a context-dependent manner. Thus, although autophagy stands out as a major target to intercept cancer at multiple inflection points of the disease, one-size-fits-all approaches are inherently incapable of capturing the complex influence of autophagy on the cancer cell (immuno)biology as a whole. Further complicating this scenario, healthy cells, including tumour-targeting immune effectors, rely on autophagy for their maturation, survival and functions, and pharmacological autophagy inhibitors currently available for use in humans are intrinsically nonspecific. Here, we discuss the promise and limitations of targeting autophagy to limit malignant transformation, exacerbate cancer cell death as driven by conventional therapeutics and restore immunosurveillance in support of superior disease responses to immunotherapy.
    DOI:  https://doi.org/10.1038/s41573-026-01449-9
  3. Autophagy. 2026 May 21.
    High-fat diet exacerbates experimental colitis by inhibiting lysosomal function via the STAT3-TFEB Axis.
    Haodong He, XingZhou Guo, Miao Xu, Zongbiao Tan, Chen Tan, Xiangyun Li, Zixuan Xiang, Pengzhan He, Beiying Deng, Yu Pu, Yafei Liu, Luyun Zhang, Jixiang Zhang, Weiguo Dong.
      An elevated risk for inflammatory bowel disease (IBD) has been linked to the intake of high-fat diet (HFD), yet the underlying molecular mechanisms remain unclear. The lysosome and the macroautophagy/autophagy-lysosome pathway (ALP) are critical for maintaining the intestinal epithelial barrier. By employing both an in vivo model of dextran sulfate sodium (DSS)-induced colitis in mice and an in vitro model using lipopolysaccharide (LPS)-treated NCM460 cells, we established that HFD in vivo and palmitic acid (PA) in vitro profoundly impair epithelial barrier function and amplify inflammation, which was linked to the suppression of lysosomal function and the ALP. Mechanistically, HFD in vivo and PA in vitro activated STAT3 (p-STAT3[Y705]) under DSS- and LPS-associated inflammatory stress, respectively. This led to a dual suppression of TFEB: on the one hand, activated STAT3 directly bound to the TFEB promoter to inhibit its transcription; on the other hand, it facilitated the lysosomal recruitment of MTOR and activated MTORC1, which promoted TFEB phosphorylation (p-TFEB[S211]) and hindered its nuclear translocation. This cascade resulted in lysosomal membrane permeabilization (LMP), loss of acidification, and impaired degradative function. Intestinal epithelial-specific knockout of Stat3 or pharmacological activation of TFEB restored lysosomal function, repaired the epithelial barrier, and ameliorated colitis. Conversely, rectal administration of AAV9-shTfeb reversed the protective effects conferred by stat3 knockout. Our study reveals that HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD. Abbreviations: AB-PAS: Alcian blue-periodic acid-Schiff; ALP: autophagy-lysosome pathway; CD: Crohn disease; ChIP: chromatin immunoprecipitation; CLEAR: coordinated lysosomal expression and regulation; DSS: dextran sulfate sodium; HFD: high-fat diet; IBD: inflammatory bowel disease; IF: immunofluorescence; IHC: immunohistochemistry; LAMP: lysosome associated membrane protein; LGALS3/Gal3: galectin 3; LMP: lysosomal membrane permeabilization; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PA: palmitic acid; RRAG: Ras-related GTP binding; RRAG-CA: constitutively active RRAG GTPase; RT-qPCR: reverse transcription quantitative PCR; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TA1: TFEB activator 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; TJ: tight junction; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UC: ulcerative colitis; WB: western blot; WT: wild-type.
    Keywords:  Autophagy-lysosome pathway; MTORC1; STAT3; TFEB; high-fat diet; intestinal epithelial barrier; lysosome; ulcerative colitis
    DOI:  https://doi.org/10.1080/15548627.2026.2678426
  4. Autophagy. 2026 Jun;22(6): 1149-1150
    Identification of a conserved receptor for degrading ribosomes through autophagy.
    Chhabi K Govind, Daniel J Klionsky.
      Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria.Abbreviations: AIM: Atg8-family interacting motif; ATG: autophagy related; LIR: LC3-interacting region; NUFIP1: nuclear FMR1 interacting protein 1.
    Keywords:  Autophagy; Rpl12A; ribophagy; ribosomes; starvation
    DOI:  https://doi.org/10.1080/15548627.2026.2624242
  5. Autophagy. 2026 May 19. 1-22
    FGF21 rejuvenates aged human adipose-derived mesenchymal stem cells via enhancement of TFE3-mediated autophagy flux.
    Bei Song, Chengyun Liu, Jingqiong Hu, Xiaofang Zhao, Haohui Fan, Ting Liu, Guangyu Gao, Xinyue Zhang, Xueke Guang, Quan Zhou, Kun Wang, Weilin Lu.
      Intracerebral hemorrhage (ICH) is a neurological disorder characterized by a high mortality rate for which there is currently no definitive cure. Research has demonstrated that adipose-derived mesenchymal stem cells (ASCs) exhibit considerable potential in treating ICH. However, the advanced age of ICH patients and the necessary cell expansion before transplantation therapy could result in the senescence of ASCs, thereby compromising their viability and therapeutic efficacy. This study aims to investigate whether FGF21 (fibroblast growth factor 21) can rejuvenate aged ASCs by enhancing macroautophagy/autophagy flux and subsequently enhance the therapeutic efficacy of ICH. We demonstrated that the autophagy flux of aged ASCs was significantly decreased and FGF21 treatment significantly reversed the senescence phenotype and increased the viability of aged ASCs. Mechanistically, our findings suggested that FGF21 rejuvenates aged ASCs by augmenting autophagy flux, a process partly mediated by TFE3 (transcription factor E3) nuclear translocation. The FGF21-induced TFE3 nuclear translocation was partially facilitated potentially via the FGFR1-SIRT1-MTOR pathway. In addition, FGF21 enhanced the potential of senescent ASCs to differentiate into neurons. In the in vivo study, we further verified that FGF21 could enhance the therapeutic effect of ASCs on acute ICH rats. In conclusion, these results indicated that FGF21 could restore ASC viability by upregulating TFE3-mediated autophagy flux in part through the FGFR1-SIRT1-MTOR signaling pathway, enhanced the potential to improve the differentiation of ASCs into neural stem cells and enhanced the therapeutic effect of ASCs transplantation in acute ICH.Abbreviations: FGF21: fibroblast growth factor 21; TFE3: transcription factor E3; TFEB: transcription factor EB; DMEM: Dulbecco's modified Eagle medium; RAPA: rapamycin; 3-MA: 3-methyladenine; CQ: chloroquine; DMSO: dimethyl sulfoxide; RT-qPCR: quantitative real-time PCR; pAb: polyclonal antibody; mAb: monoclonal antibody; LAMP1: lysosomal associated membrane protein 1; SQSTM1/p62: sequestosome 1; MAP1lc3/LC3: microtubule associated protein 1 light chain 3; GFAP: glial fibrillary acidic protein; MAP2: microtubule associated protein 2; SOX2: SRY-box transcription factor 2; MOI: multiplicity of infection; FGFR1: fibroblast growth factor receptor 1; SIRT1: sirtuin 1; MTOR: mechanistic target of rapamycin kinase; ROS: reactive oxygen species; siRNA: small interfering RNA; OD: optical density; SASP: senescence-related secretion phenotype; IL6: interleukin 6; IL1B/IL-1β: interleukin 1 beta; TNF/TNF-α: tumor necrosis factor; CCL2/MCP-1: C-C motif chemokine ligand 2; BDNF: brain derived neurotrophic factor; VEGF: vascular endothelial growth factor; ICH: intracerebral hemorrhage; MLPT: modified limb placement test.
    Keywords:  ASCs; FGF21; TFE3; autophagy flux; intracerebral hemorrhage
    DOI:  https://doi.org/10.1080/15548627.2026.2669987
  6. Acta Neuropathol. 2026 May 20. pii: 60. [Epub ahead of print]151(1):
    The phosphoproteomic landscape of the neurological manifestations in tuberous sclerosis complex.
    Marie Girodengo, Simeon R Mihaylov, Katarzyna Klonowska, Laura Mantoan Ritter, Helen R Flynn, J Mark Skehel, Elias Bou Farhat, Eleonora Aronica, Matthew White, David J Kwiatkowski, Sila K Ultanir, Joseph M Bateman.
      Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in TSC1 and TSC2, resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations in TSC patients include epilepsy, autism and intellectual disability. Two types of brain lesions, cortical tubers and subependymal giant cell astrocytomas (SEGAs), cause the majority of neurological manifestations in TSC. We have limited understanding of the molecular changes that occur in tubers and SEGAs and how these contribute to disease pathogenesis. To investigate this, we performed proteomic and phosphoproteomic analysis of TSC patient tuber and SEGA tissue. Tubers showed evidence of alterations in mitochondrial respiration, cytoskeleton organisation and neuronal function. However, we were unable to detect mTORC1 activation in tubers, likely due to the small number of cells with complete inactivation of TSC1 or TSC2. By contrast, SEGAs showed evidence of strong mTORC1 activation and large-scale changes in the proteome and phosphoproteome. SEGAs exhibited increased expression of ribosomal proteins and activation of a neuroinflammatory response. Phosphoproteomics identified 6060 phosphosites within 2154 proteins increased in SEGAs. Phosphorylation of multiple proteins involved in RNA-metabolism, including mRNA splicing, was increased in SEGAs. Consistent with this, we found evidence of extensive alterations in mRNA transcript splicing in SEGA tissue that is shared with a wide range of cancers. These data greatly expand the repertoire of known mTORC1 target proteins in the human brain and reveal that large-scale mis-regulation of mRNA splicing may promote the formation of SEGAs in TSC.
    Keywords:  Phosphoproteomics; SEGA; Signalling; TSC; Tuber; mTOR
    DOI:  https://doi.org/10.1007/s00401-026-03022-5
  7. Nat Commun. 2026 May 22.
    Chaperone-mediated autophagy is required for regulatory T cell function.
    Ranee Harrison, Floralba Gjergjova, Sandra Pelka, Adrian Macho-Gonzalez, Bhakti Chavda, Kristen Lindenau, Aiara Gazteluiturri Garcia, Rabia R Khawaja, Jennifer T Aguilan, Simone Sidoli, Susmita Kaushik, Yair Botbol, Ana Maria Cuervo, Fernando Macian.
      Chaperone-mediated autophagy (CMA) is a selective form of protein degradation in lysosomes that declines with age. Besides protein quality control, CMA also regulates several cellular processes through timely proteome remodeling. We previously demonstrated the importance of CMA in the activation of helper T cells. In this work, we analyzed the role of CMA in the generation and function of regulatory T cells (Tregs), a specialized type of T cells that suppress immune responses. We found that the basal CMA activity of Tregs further increases upon their activation. Using a Treg-specific CMA-deficient mouse model, we show that CMA is crucial for maintenance of peripheral tolerance by Tregs. Mice with CMA-defective Tregs display signs of chronic inflammation, which results in reduced survival as they age. We demonstrate that CMA-deficient Tregs have reduced suppressive activity in vivo using an experimental model of inflammatory bowel disease and a second model of tumor-induced immune response. Comparative quantitative proteomic analysis enabled us to identify the subproteome degraded by CMA and, consequently, the cellular pathways modulated by this type of autophagy to sustain Treg homeostasis and function. Collectively, our findings uncover a previously unknown role for CMA in regulating Treg function.
    DOI:  https://doi.org/10.1038/s41467-026-73417-1
  8. J Cell Biol. 2026 Jul 06. pii: e202509040. [Epub ahead of print]225(7):
    Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis.
    Priya Chouhan, Yogita Phogat, Kshitiz Walia, Saikat Debnath, Sandeep Choubey, Medha Gupta, Amit Tuli, Mahak Sharma.
      The small GTP-binding protein Arl8b is established as a regulator of lysosome positioning and fusion, yet its role in lysosome biogenesis remains unclear. Here, we investigate the role of Arl8b in the trafficking of newly synthesized LAMP1 to lysosomes using the Retention Using Selective Hook (RUSH) assay. We find that Arl8b localizes to post-endocytic LAMP1-containing vesicles prior to fusion with acidic lysosomes. Arl8b depletion leads to Rab11a-dependent recycling of LAMP1 to the plasma membrane, impairing its lysosomal delivery. Mechanistically, Arl8b recruits the Rab11a GAP, TBC1D9B, to LAMP1-positive membranes, and TBC1D9B depletion similarly disrupts LAMP1 sorting. Notably, TBC1D9B knockdown also impairs the retrieval of cation-independent mannose-6-phosphate receptor (CI-M6PR) from Rab11a- and Rab14-positive endosomes to the trans-Golgi network, impairing pro-cathepsin trafficking and cargo degradation. These findings reveal that Arl8b-mediated recruitment of Rab GAP TBC1D9B is crucial for inactivation of the Rab11a recycling pathway, leading to efficient sorting of lysosomal cargo to their functional location.
    DOI:  https://doi.org/10.1083/jcb.202509040
  9. Aging Cell. 2026 Jun;25(6): e70550
    Methionine Restriction Extends Yeast Lifespan by Activating Non-Nitrogen-Starvation-Induced Autophagy Through Limiting Methylation of Protein Phosphatase 2A.
    Kaylah Birmingham, Nina Arslanovic, Thea Grauer, Ignacio Gutierrez, Ujani Chakraborty, Simone Sidoli, Jessica Tyler.
      Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosylmethionine (SAM). Mechanistically, the key antiaging event downregulated by MR is the methylation of protein phosphatase 2A (PP2A). In chronological aging cells under MR, unmethylated PP2A no longer dephosphorylates Npr2, a component of the SEACIT complex, resulting in activation of non-nitrogen-starvation (NNS)-induced autophagy. Deletion of genes encoding components of SEACIT or ATG1 (encoding a central player in the initiation of autophagy) blocked the ability of MR to extend lifespan, showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR. We identify the relevant Npr2 site dephosphorylated by PP2A as serine 362 and show that Npr2 phosphomimetic mutants are sufficient to extend chronological and replicative lifespan. Finally, we discover that MR only during the early stages of chronological aging is sufficient to prolong autophagy and extend lifespan. In addition to elucidating the molecular mechanism of MR-mediated lifespan extension, this study highlights potential therapeutic targets to achieve lifespan and healthspan extension in humans without the challenging long-term dietary changes required to achieve MR.
    Keywords:  autophagy; lifespan; longevity; methionine restriction; methylation; phosphorylation
    DOI:  https://doi.org/10.1111/acel.70550
  10. Autophagy. 2026 May 18.
    Byakangelicin alleviates metabolic dysfunction-associated steatohepatitis by selective inhibition of non-canonical MTORC1 signaling pathway.
    Xiliang Du, Zhiyuan Fang, Guowen Liu, Li Wang, Lingxue Ju, Wenwen Gao, Yuxiang Song, Lin Lei, Xinwei Li.
      Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading cause of chronic liver disease. MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) is a potential therapeutic target, whereas suppression of total MTORC1 activity can lead to unwanted effects. Here, we found that byakangelicin (Bya), a natural compound, selectively inhibited MTORC1-mediated phosphorylation of TFEB (transcription factor EB), without affecting canonical MTORC1 substrates. Knockout of hepatic Tfeb blocked the alleviation effects of Bya on hepatic steatosis, inflammation, insulin resistance, and fibrosis in mice, while reintroduction of TFEB restored these effects. We identified Bya directly bound to MET370 and PHE552 of FLCN (folliculin), suppressing the function of the FLCN-FNIP1 (folliculin interacting protein 1)/FNIP2 complex, which in turn inhibited MTORC1-mediated cytoplasmic sequestration of TFEB. Mutation of FLCN (M370A and F552A) in the liver abolished Bya-induced protection against MASH. Thus, Bya is a promising therapeutic natural compound for MASH, and selective inhibition of MTORC1 is a potential approach to treat this disease.
    Keywords:  Autophagy; FLCN; TFEB; fatty liver; natural compound
    DOI:  https://doi.org/10.1080/15548627.2026.2676072
  11. Autophagy. 2026 May 19. 1-16
    A fetus with severe developmental defects caused by dominant-negative and hypomorphic ATG7 alleles.
    Marion Carpentier, Nicolas Chatron, Isabelle Rouvet, Pauline Monin, Béatrice Nadaud, Auragen Consortium, Damien Sanlaville, Julien Courchet, Flavie Strappazzon.
      Macroautophagy/autophagy is a fundamental process for neuronal homeostasis, yet its role in human development, notably brain development, remains poorly understood. Here, we report a fetus presenting severe developmental defects, including brain malformations, carrying two deleterious variants in ATG7, a gene associated with severe neurodevelopmental disorders: maternally inherited nonsense mutation Arg659Ter (hereafter R659*) and a de novo missense mutation Arg481Gln (hereafter R481Q). Functional analyses showed ATG7R659* acting as a dominant-negative allele, whereas ATG7R481Q was hypomorphic, revealing arginine 481 as a critical residue for ATG7-LC3 interaction in mammals. Loss of ATG7 function disrupted autophagosome formation, promoted abnormal axonal elongation and branching in neurons, and nearly abolished canonical autophagy in fetal cells. These findings highlight ATG7 as a key regulator of development and provide mechanistic insight into autophagy-related neurodevelopmental disorders.Abbreviations: ATG: autophagy related; CHX: cycloheximide; cHBSS: complete Hanks' buffered salt solution; C572A: Cys572Ala catalytically-inactive mutant; DIV: day in vitro; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; MAP1LC3: microtubule associated protein 1 light chain 3; NDD: neurodevelopmental disorder; NMD: nonsense-mediated decay; PB: permeabilization buffer; PBS: phosphate-buffered saline; RT-PCR: reverse transcriptase polymerase chain reaction; R481Q: Arg481Gln; R659*: Arg659Ter; shRNA: short hairpin RNA; siRNA: small interfering RNA.
    Keywords:  ATG7; cortical neurons; fetus; macroautophagy; neurodevelopment; variant
    DOI:  https://doi.org/10.1080/15548627.2026.2673172
  12. Cell Death Dis. 2026 May 19.
    E2F-mediated activation of mTORC1 through the ubiquitin-proteasome system promotes lung adenocarcinoma progression.
    Wentao Xue, Mengen Wang, Tong Hu, Shina Guo, Anchi Hu, Yan Gu, Hongchang Wang, Guang Mu, Wenhao Zhang, Chenghao Fu, Zizhang Guo, Ke Wei, Yanan Li, Jun Wang.
      Lung adenocarcinoma (LUAD) is the major histological subtype of non-small cell lung cancer (NSCLC). The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of anabolic growth and metabolism, has been implicated in unfavorable prognosis and therapeutic resistance in LUAD. Nevertheless, how this association is mechanistically established remains insufficiently understood. Here, by integrating TCGA/GEO datasets with our institutional LUAD single-cell RNA-seq, we identified the atypical E2F factor E2F8 as the member most closely associated with the mTORC1 pathway and found that E2F8 is upregulated in LUAD and that higher E2F8 levels correlate with adverse clinicopathological features and poorer prognosis. In PC-9 and H1975 cells, E2F8 overexpression enhanced proliferation, clonogenicity, migration, and xenograft growth, whereas E2F8 silencing produced the opposite effects; rapamycin partially reversed these phenotypes, indicating mTORC1 dependence. Mechanistically, E2F8 activated transcription of the HECT-type E3 ligase WWP1, which recognized PPxY-containing TSC1 and mediated K48-linked polyubiquitination at K662, promoting proteasomal degradation of TSC1 and sustaining mTORC1 signaling, as evidenced by increased p-mTOR (Ser2448), p-S6K1, and p-4EBP1. WWP1 knockdown markedly blunted E2F8-induced mTORC1 activation, preserved TSC1 abundance, and attenuated downstream mTORC1 readouts under E2F8/WWP1 activation, supporting TSC1 as the critical substrate. Pharmacologic WWP1 inhibition with indole-3-carbinol (I3C) restored TSC1, reduced p-mTOR (Ser2448), and suppressed LUAD xenograft growth, defining an E2F8-WWP1-TSC1-mTORC1 axis as a targetable circuit in LUAD.
    DOI:  https://doi.org/10.1038/s41419-026-08863-2
  13. Autophagy. 2026 May 20. 1-18
    Iterative design leads to a smart probe capable of quantifying autophagic flux with switchable fluorescence via engaging MAP1LC3/LC3.
    Yaping Lu, Ning Wang, Meihui Liu, Zhepei Lu, Shiqi Fan, Weisong Lv, Yingmei Lu, Feng Han, Xin Li.
      Tracking macroautophagic/autophagic flux in live cells is vital for understanding its pathophysiology; however, its dynamic nature complicates assay development. Although fluorescent protein-tagged markers and microenvironment-sensitive small-molecule fluorescent probes have been developed, non-transfection-based and highly specific assays remain underexplored. In this study, we present the design, synthesis, and application of an activity-based autophagy probe (ATP1) for dynamically quantifying autophagic flux. ATP1 was developed through an iterative, docking-guided design strategy to secure MAP1LC3/LC3 engagement, coupled with in-depth analysis of structure-fluorescence relationships to program dual smart-signal behaviors. It displays LC3-binding-triggered fluorogenic activation and autophagosome-lysosome fusion-triggered ratiometric changes. By engaging LC3, the probe is inherently specific to autophagy, and its dynamic signal enables real-time tracking of autophagic flux with high sensitivity. We demonstrate ATP1's exceptional performance in live cells and mice, with a dynamic signal paralleling the mRFP-GFP-LC3 assay. Notably, ATP1 provides significant benefits, including low background signals, compatibility with primary cells, and effectiveness in wild-type mice, where transfection-based assays are often impractical. Furthermore, the probe aids in the discovery of autophagy modulators. In conclusion, ATP1 offers a straightforward, specific, and non-transfection-based method for assessing autophagic flux, serving as a powerful tool for advancing autophagy research.Abbreviations: 3-MA: 3-methyladenine; ATP: autophagy probe; BafA1: bafilomycin A1; CBF: cerebral blood flow; FP: fluorescent protein; HBMECs: human brain microvascular endothelial cells; HBSS: Hanks' balanced salt solution; HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; ITC: isothermal titration calorimetry; LIR: LC3-interacting region; LSCI: laser speckle contrast imaging; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; OGD: oxygen-glucose deprivation; PBS: phosphate-buffered saline; Rapa: rapamycin; Wort: wortmannin.
    Keywords:  Autolysosome; autophagosome; autophagy imaging; fluorescent probe; microtubule-associated protein 1 light chain 3; ratiometric signal
    DOI:  https://doi.org/10.1080/15548627.2026.2674717
  14. Mitochondrion. 2026 May 19. pii: S1567-7249(26)00061-9. [Epub ahead of print] 102171
    Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
    Yu-Ting Wu, Hui-Yi Tay, Hsiao-Hui Liao, Jung-Tse Yang, Yau-Huei Wei.
      Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A > G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A > G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.
    Keywords:  MERRF syndrome; Mitophagy; N-acetylcysteine; PINK1; iPSC-derived neural stem cells (iNSCs); iPSC-derived neurons; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.mito.2026.102171
  15. Cell Biol Toxicol. 2026 May 21.
    Mechanisms of TRIM21-mediated RUNX2 degradation via chaperone-mediated autophagy in periodontitis.
    Yi Zhao, Yuyu Ge, Qiaoli Zhai, Zhiqiang Wang.
      The osteogenic capability of periodontal ligament cells in periodontitis is impaired partly due to decreased RUNX2 expression. Mass spectrometry identified TRIM21 as a protein that interacts with RUNX2 and facilitates its degradation. Pharmacological inhibition experiments revealed that blocking the lysosomal pathway significantly attenuated TRIM21-mediated RUNX2 degradation, whereas inhibition of the proteasome or macroautophagy had no such effect. Subsequent analysis revealed that the KFERQ-like motif in TRIM21 is crucial for its identification in chaperone-mediated autophagy (CMA). TRIM21 mutants lacking this motif failed to bind the chaperone protein HSC70 and could not mediate RUNX2 degradation. HSC70 identifies the KFERQ motif in TRIM21, aiding the transport of the TRIM21-RUNX2 complex to lysosomal-associated membrane protein 2A (LAMP2A) on the lysosome surface, which promotes RUNX2 degradation. In conclusion, our study demonstrated that TRIM21 mediated RUNX2 degradation through the lysosome-mediated CMA, driven by its interaction with HSC70 via the KFERQ motif. This mechanism is exacerbated in periodontitis due to elevated TRIM21 expression, leading to reduced RUNX2 levels. These findings provide new insights into the impaired osteogenic capacity in periodontitis and highlight TRIM21 as a potential therapeutic target to restore RUNX2 function and enhance bone regeneration in periodontal disease.
    Keywords:  Chaperone-mediated autophagy; HSC70; LAMP2A; Periodontitis; RUNX2; TRIM21
    DOI:  https://doi.org/10.1007/s10565-026-10209-9
  16. Cell Mol Life Sci. 2026 May 23. pii: 224. [Epub ahead of print]83(1):
    mTORC1-signaling switches megalin function from endocytosis to cell cycle progression.
    Eileen Dahlke, Madlen Kunke, Hannah Knöfler, Yaman Anan, Yuanhao Shen, Danyang Zhao, Christine von Toerne, Franziska Theilig.
      Mechanistic target of rapamycin (mTOR) signaling pathway controls eukaryotic growth by regulating metabolism, translation, autophagy and cell cycle. Genetic deletion of renal mTORC1 led to a Fanconi-like syndrome with reduction of the renal cortex, tubular epithelial transport and perturbation of the endocytic machinery. Although the main scavenger receptor megalin remained unaltered, a new phosphorylation site at S4577 was found. The identification of the role of this mTORC1-induced phosphorylation on megalin was subject of our analysis. mTORC1-induced megalin phosphorylation reduced endocytosis rate with only minor distribution changes. It augmented the affinity of megalin to the adaptor protein ARH with consecutively increased proteolytic processing of megalin C-terminal domain and favored cell proliferation. During cell mitosis megalin is localized with ARH at the spindle pole. Compared to wildtype cells, megalin-deficient and ARH-deficient cells showed significantly less cell proliferation, and during cytokinesis significantly less ARH or megalin signals, respectively at the pole of intercellular bridges. mTORC1-induced megalin S4577 phopshorylation varies throughout the cell cycle with highest abundance in metaphase and telophase/cytokinesis. Both, lysosomal and non-lysosomal (external) nutrient supply influence cell proliferation to different extent. In conclusion, absence of the mTORC1-induced megalin S4577 phosphorylation favors cell growth and clathrin-mediated endocytosis whereas mTORC1-induced megalin phosphorylation at S4577 favors cell proliferation and increases the affinity to the adaptor protein ARH for proper cell division. Especially, during cytokinesis megalin and ARH ensure trafficking of membrane vesicles towards the pole of intercellular bridges most probably for the terminal abscission process.
    Keywords:  Clathrin; Kidney; LRP2; Metaphase; Proteolytical cleavage; Proximal tubule
    DOI:  https://doi.org/10.1007/s00018-026-06247-5
  17. Autophagy. 2026 May 19.
    Feedback loops between DNMT1 and autophagy as well as senescence promotes organ aging and canities.
    Lu Li, Xinyue Mao, Linda Xiaoyan Li, Huaping Xiao, Zhenkun Lou, Hongbo Liu, Julie Xia Zhou, Li Yao, Xiaogang Li.
      Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in the mammalian genome, is reported to be decreased in an age-dependent manner, the decrease of Dnmt1 mRNA does not result in a decrease of its protein. Instead, DNMT1 protein is increased in aged mouse tissues, which is responsible for the methylation of genes related to macroautophagy/autophagy, senescence repression, and melanin synthesis and transport in aged organs, resulting in a decline of autophagy, an increase of senescence in those organs, and a decrease in melanin production in hair follicles (canities) in response to ionizing radiation (IR). Genetic deletion and inhibition of DNMT1 can reverse these processes. The interaction of DNMT1 with ATG7 through its CXXC domain is essential for its degradation, and treatment with senolytics also downregulates DNMT1 in aged organs, supporting two feedback loops between them.
    Keywords:  ATG7; DNA methylation; hair graying; long-lived; melanin synthesis; senolytics
    DOI:  https://doi.org/10.1080/15548627.2026.2677185
  18. FASEB J. 2026 May 31. 40(10): e71905
    LAPTM5 Promotes Age-Related Renal Fibrosis via USP10/PTEN-Mediated Autophagy Inhibition.
    Yan Wang, Qian Gu, Xueqi Chen, Xiaowei Yang, Jiajia Zhai, Meizi Kang, Jianqing Wu, Weihong Zhao.
      Aging accelerates renal fibrosis driven by renal tubular epithelial cells (RTECs) senescence. However, the underlying molecular mechanisms remain elusive. We demonstrate that lysosomal transmembrane protein 5 (LAPTM5) is markedly upregulated in aged kidney models and correlates with renal senescence and fibrosis severity. Mechanistically, LAPTM5 drives RTECs epithelial-mesenchymal transition (EMT) by interacting with USP10 and facilitating its lysosomal degradation, thereby relieving PTEN-mediated inhibition of the PI3K/AKT/mTOR-mediated autophagy pathway. This accelerates kidney fibrosis. Functionally, PTEN overexpression rescues LAPTM5-induced EMT in RTECs, while the PTEN agonist sophocarpine ameliorates renal fibrosis and preserves function in D-galactose-induced progeroid mice by restoring autophagy. Our findings identify the LAPTM5-USP10-PTEN axis as a critical regulator of autophagy-mediated renal fibrosis in aging kidney.
    Keywords:  LAPTM5; PI3K/AKT/mTOR; PTEN; autophagy; fibrosis; kidney; renal tubular epithelial cells; senescence; sophocarpine
    DOI:  https://doi.org/10.1096/fj.202504863RR
  19. Sci Adv. 2026 May 22. 12(21): eaeb8658
    Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.
    Ryan M Loughran, Gurpreet K Arora, Jiachen Sun, Alicia Llorente, Sophia Crabtree, Cynthia Y Zhang, Kyanh Ly, Ren-Li Huynh, Wonhwa Cho, Brooke M Emerling.
      In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P2 at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mechanistic target of rapamycin (mTOR) pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.
    DOI:  https://doi.org/10.1126/sciadv.aeb8658
  20. Sci Transl Med. 2026 May 20. 18(850): eadj4902
    Real-time in vivo analysis of murine β cells reveals autophagic flux defects before onset of autoimmune diabetes.
    Olha Melnyk, Charanya Muralidharan, Bryce E Duffett, Alissa N Muncy, Leslie E Wagner, Matthew Austin, Jahnavi Aluri, Abdul S Qadir, Yashaswini Battina, Rachael Morara, Glorian Perez-Aviles, Justin J Crowder, Michelle M Martinez-Irizarry, Sylvaine You, Roberto Mallone, Amelia K Linnemann.
      Autophagy, a vital catabolic process, plays a crucial role in maintaining pancreatic β cell function and is disrupted in established type 1 diabetes. However, it is unclear when and how this critical cell process becomes defective during type 1 diabetes pathogenesis. To study the nature of autophagy dysfunction in the context of autoimmune diabetes, we used real-time intravital microscopy to study autophagic flux in vivo. We generated an AAV8-packaged mCherry-eGFP-LC3B biosensor driven by the insulin promoter for β cell-selective expression. For real-time autophagic flux evaluation, fluorescent signals from eGFP and mCherry fluorophores were correlated in space and time to follow the process of autophagosome-lysosome fusion. We observed autophagic flux defects in the β cells of the nonobese diabetic (NOD) mouse model of type 1 diabetes before hyperglycemia onset at both baseline and in response to interferon-α. These defects were still present, although less apparent, in immunodeficient NOD/scid/il2rg (NSG) mice. We also observed heterogeneous autophagic flux in human donor islets transplanted under the kidney capsules of NSG mice. In sum, the ability to visualize autophagic flux in β cells over time in vivo revealed impairments in those β cells that preceded the onset of autoimmune diabetes.
    DOI:  https://doi.org/10.1126/scitranslmed.adj4902
  21. J Biol Chem. 2026 May 15. pii: S0021-9258(26)02037-5. [Epub ahead of print] 113165
    Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.
    Ningda Xu, Xiangpeng Wang, Jiyue Zhang, Jianxin Zhao, Sheng Yan, Wen Zhou, Wei Chi, Jing Li.
      O-linked β-N-acetylglucosamine (O-GlcNAc) functions as a nutrition rheostat to mediate cellular signaling pathways. It fluctuates in response to various nutritional factors, for instance, glucose availability. Previous investigations have shown that glucose deprivation upregulates O-GlcNAcylation levels. Meanwhile, starvation also activates autophagy, in particular, chaperone-mediated autophagy (CMA). But it is unknown what signal activates CMA during starvation. In the CMA pathway, heat shock cognate 70 kDa protein (HSC70) recognizes client proteins that bear a KFERQ pentapeptide motif, and delivers them for lysosomal degradation. Herein we show that glucose depletion increases both the affinity between HSC70 and O-GlcNAc transferase (OGT), and HSC70 O-GlcNAcylation levels. We validated that HSC70 is O-GlcNAcylated at T430 according to a previous chemoproteomic screen. We further demonstrate that O-GlcNAcylation attenuates HSC70 stability, but increases its binding with known CMA substrates, such as PKM2. We thus posit that starvation-induced HSC70 O-GlcNAcylation may activate CMA. To test this, we used label-free quantitative mass spectrometry to analyze HSC70-WT and HSC70-T430A interactome, and obtained a proteome-wide potential CMA substrate pool. By studying this dataset, we identified a new CMA substrate, Ataxin-10, a protein involved in a neurologic disorder. We then validated our model by mapping a potential KFERQ motif on Ataxin-10 and showing that HSC70-T430A decreased binding with Ataxin-10. In sum, our work suggests that CMA and O-GlcNAcylation intersect at HSC70, and starvation-induced O-GlcNAcylation of HSC70 is part of the signal that activates CMA during fasting.
    Keywords:  Ataxin-10; HSC70; O-GlcNAc; chaperone-mediated autophagy; starvation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113165
  22. J Alzheimers Dis. 2026 May 21. 13872877261452598
    An aging hallmark, Alzheimer's disease, and APOE nexus.
    Alexander P Gabrielli, Ian Weidling, Colton R Lysaker, Lesya Novikova, Amol Ranjan, Xiaowan Wang, Heather M Wilkins, Russell H Swerdlow.
      BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. APOE biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing) to APOE biology.MethodsWe altered SH-SY5Y cell proteostasis directly via heat shock, integrated stress response inhibition (ISRIB), or autophagy inhibition (chloroquine), and indirectly by perturbing mitochondria (mtDNA depletion; oligomycin). We also exposed induced pluripotent stem cell-derived neurons to ISRIB and chloroquine. Conversely, we mitigated protein stress with rapamycin. We assessed intervention impact on APOE expression.ResultsIncreasing protein stress elevated and decreasing protein stress lowered APOE expression. In SH-SY5Y cells rapamycin blocked oligomycin-induced mTOR 2448 phosphorylation, Akt 473 phosphorylation, and APOE expression. In chloroquine-treated neurons rapamycin reduced mTOR phosphorylation and APOE expression.DiscussionProtein stress initiates APOE expression and facilitates mitochondrial dysfunction's impact on APOE by engaging the mTOR pathway. Our findings link aging and AD biology.
    Keywords:  APOE; Alzheimer's disease; mTOR; mitochondria; proteostasis; rapamycin
    DOI:  https://doi.org/10.1177/13872877261452598
  23. Mol Neurodegener. 2026 May 16.
    Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.
    Prabhavathi Maddineni, Balasankara Reddy Kaipa, Bindu Kodati, Karthikeyan Kesavan, Linya Li, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode.
       BACKGROUND: Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma. We further explore the therapeutic potential of enhancing autophagy to improve mitochondrial turnover, mitigate RGC loss, and preserve visual function.
    METHODS: Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers (TOM20/COX IV), oxidative DNA damage (8-OHdG), and mitophagy/autophagy-related proteins (p62, LC3, Phospho-ubiquitin (Ser65), and LAMP1) in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation in glaucomatous ON. Mitophagy flux was assessed at early and late stages of neurodegeneration using mitophagy reporter Mt-Keima mice. The effect of RGC-specific autophagy deficiency on mitochondrial accumulation and neurodegeneration was further investigated using Atg5flox/flox mice, in which Atg5 deletion was induced by AAV2-Cre delivery. Additionally, the therapeutic effect of enhancing autophagy with Torin 2 to restore mitochondrial turnover and prevent glaucomatous neurodegeneration was evaluated in both GC-induced and myocilin-associated glaucoma models, as well as in ex vivo human retinal explants.
    RESULTS: Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In Mt-Keima mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration. RGC-specific Atg5 deletion induced the accumulation of damaged mitochondria, leading to neurodegeneration in Atg5 flox/flox mice. Notably, pharmacological restoration of impaired autophagy with Torin 2 prevented mitochondrial accumulation and preserved the structural and functional integrity of RGCs and their axons in glaucoma mouse models and ex vivo human retinal explant cultures.
    CONCLUSION: Our study indicates impaired autophagy contributes to damaged mitochondrial accumulation and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing autophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.
    Keywords:  Autophagy; Glaucoma; Intraocular pressure; Mitochondrial dysfunction; Mitophagy; Mouse models of glaucoma; Neurodegeneration; Optic neuropathy; Oxidative DNA damage; Torin 2
    DOI:  https://doi.org/10.1186/s13024-026-00950-4
  24. Dev Dyn. 2026 May 21.
    Spatiotemporal dynamics of mTORC1 and mTORC2 in the developing spinal cord and their essential roles in gliogenesis.
    Rina Sasaki, Noriaki Sasai, Takuma Shinozuka.
       BACKGROUND: Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase with diverse roles in development and homeostasis, but its spatiotemporal dynamics in the embryonic spinal cord are not fully defined. Here, we map mTOR activity across mouse spinal cord development and test its function using a conditional gene mutant.
    RESULTS: Immunohistochemistry for phosphorylated readouts of mTORC1 and mTORC2 revealed distinct, stage-dependent patterns. In the early neural tube, phosphorylated S6 (p-S6; Ser235/236 and Ser240/244) marked dorsal progenitors and ventral motor neurons, while p-p70S6K, p-4E-BP1, and p-Akt (Ser473) were enriched along the luminal surface where mitoses occur. By E13.5, p-S6 persisted in the motor column, whereas p-p70S6K, p-4E-BP1, and luminal p-Akt remained ventricular; at E18.5, robust p-S6 and p-p70S6K signals were localized to neuronal somata and fibers in the marginal layer, with minimal p-Akt. Closer examination revealed that mTORC1/2 signals preferentially colocalized with pHH3-positive ventricular progenitors early, then decoupled as development progressed. Within motor neurons, mTORC1 broadly overlapped with Islet1, including the Lhx3-positive medial motor column (MMC), whereas mTORC2 (p-Akt) labeled an Islet1-positive subset complementary to Lhx3 and declined over time, demarcating lateral, non-MMC domains. Nestin-Cre-mediated mTOR deletion did not overtly affect neuronal organization but reduced GFAP- and Sox10-positive glial lineage cells, indicating a selective requirement of mTOR for glial differentiation.
    CONCLUSIONS: Together, the data suggest separable and temporal roles of mTORC1 and mTORC2 in progenitor mitosis, motor-neuron domain organization, and late embryonic gliogenesis.
    Keywords:  conditional knockout; glial development; mTOR; mitotic neural progenitor; motor column; neural tube
    DOI:  https://doi.org/10.1002/dvdy.70150
  25. Autophagy. 2026 May 18. 1-26
    Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion.
    Maria Dolores Salinas, Isabel Maria Martínez, Elena Naranjo, Maria Luisa Molina, Ana Maria Cuervo, Sylviane Muller, Rut Valdor.
      Glioblastoma (GB) is the most aggressive brain cancer, with poor prognosis due to infiltrative invasion of glioma stem cells (GSCs) and the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that pericytes (PCs), specialized cells in the blood microvessels surrounding GB, are conditioned by infiltrating tumor cells to aberrantly upregulate their chaperone-mediated autophagy (CMA). Elevated CMA in PCs promotes stable cell-cell interactions with tumor cells and a pro-tumoral immune phenotype that supports tumor progression. In this work, to test if inhibition of CMA in PCs might be an effective strategy to reduce tumor survival, we have used the phosphopeptide P140, known to restore aberrant CMA upregulation in specific immune cells. We found that administration of P140 peptide in an immunocompetent GB mouse model with both patient-derived GSCs and GB cell lines, neutralizes GB-induced PC CMA upregulation resulting in ablation of PC-tumor cell interactions and triggering of a secretome toxic to tumor cells. We identified MAPT/tau, a known CMA substrate, as one of the main components of this secretome, and discovered that CMA-dependent PC MAPT/tau secretion within the GB TME plays a key role in cancer progression and recurrence. Furthermore, we found that perivascular accumulation of MAPT/tau is an effective way to monitor peptide P140 treatment efficacy in GB and for prognosis of the patient evolution. Our findings validate P140 peptide treatment as a safe and specific strategy to halt GB progression and establish the clinical relevance of extracellular MAPT/tau as a biomarker for therapeutic success in GB.Abbreviations: ACTA2/ASMA: actin alpha 2, smooth muscle; BBB: blood-brain barrier; CMA: chaperone-mediated autophagy; CTLA4: cytotoxic T-lymphocyte associated protein 4; DAB: 3-3'diaminobenzidine; GB: glioblastoma; GBCPC: GB-conditioned pericyte; GSCs: glioblastoma stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosome associated membrane protein 2A; LI: lysosomal inhibitors; MAPT/tau: microtubule associated protein tau; NAc: N-acetylcysteine; PC: pericyte; PCGB: pericyte-glioblastoma coculture; PDGFRB: platelet derived growth factor receptor beta; ROS: Reactive oxygen species; SPARC: secreted protein acidic and cysteine rich; TME: tumor microenvironment; TNT: tunneling nanotubes.
    Keywords:  Chaperone-mediated autophagy; MAPT/tau; P140 peptide; glioblastoma cancer; glioma stem cells; pericytes
    DOI:  https://doi.org/10.1080/15548627.2026.2672700
  26. bioRxiv. 2026 May 05. pii: 2026.04.30.722110. [Epub ahead of print]
    Elucidating the molecular interplay between LRRK2 and Rab GTPases.
    Hanwen Zhu, Liam Eade, Dario R Alessi, Ji Sun.
      Gain-of-function mutations in LRRK2 are a major cause of inherited Parkinson's disease. LRRK2 encodes a multidomain kinase, whose bidirectional interplay with Rab GTPases regulates critical cellular processes like lysosomal homeostasis. Certain Rabs, including Rab12 and Rab29, recruit LRRK2 to organelle membranes and stimulate its kinase activity; activated LRRK2 phosphorylates a subset of Rabs in their Switch-II motifs. Molecular basis governing selective Rab recognition by LRRK2 remains unclear. Here we structurally characterize LRRK2 interactions with representative Rab GTPases and identify three novel Rab-binding sites: site 4 for Rab8A/10, site 5 for Rab43, and site 6 for Rab5A, defining a total of six distinct binding sites that account for known LRRK2-interacting Rabs. Additionally, we elucidated the binding site of GABARAP, an ATG8 member that recruits LRRK2 to stressed lysosomes. Our findings provide a framework for therapeutic targeting of LRRK2 recruitment for Parkinson's.
    DOI:  https://doi.org/10.64898/2026.04.30.722110
  27. Autophagy. 2026 May 18. 1-20
    FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration.
    Jinyu Cai, Yanmei Jiang, Xingyu Liu, Tao Yang, Peizeng Yang, Ling Chen.
      Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In apoe-/- mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the autophagy inhibitor 3-methyladenine (3-MA), but decreased with the autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased MTOR activity, thereby facilitating autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.
    Keywords:  Age-related macular degeneration; FASN; autophagy; lipid metabolism; lipophagy; retinal pigment epithelium
    DOI:  https://doi.org/10.1080/15548627.2026.2673559
  28. Autophagy. 2026 May 18.
    Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.
    Yu B Ko, Minjeong Ko, Marius Ueffing, Hye Jin Kang, Ho Jeong Kwon.
      Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for degradation. VCP overexpression supports cancer cell survival and correlates with poor prognosis, promoting the development of VCP inhibitors as anti-cancer agents. However, the molecular basis for cancer-selective vulnerability of VCP inhibition remains unclear. Here, we demonstrate that allosteric VCP inhibition triggers cell- type specific macroautophagy/autophagy through dynamic reorganization of organelle contact sites. In human umbilical vein endothelial cells (HUVECs), VCP inhibition induces adaptive autophagy through coordinated reorganization of plasma membrane (PM)-ER-mitochondria contacts. Controlled opening of the mitochondrial permeability transition pore (mPTP) releases calcium into the cytosol, activating AMP-activated protein kinase (AMPK) and TFEB pathways, collectively enhancing autophagic flux and sustaining endothelial survival. Critically, calcium-activated kinase inhibitor or calcium chelators blocked VCP inhibitor-induced autophagy in HUVECs, confirming calcium signaling as the central mediator of adaptive autophagy. In contrast, HCT116 colon cancer cells fail to maintain calcium homeostasis under VCP inhibition, leading to mitochondrial calcium overload, defective autophagy, and cell death. Together, our findings identify organelle contact reorganization and calcium homeostasis as key determinants of cell fate under conditions of proteotoxic stress, revealing how VCP inhibition selectively suppresses tumor progression while preserving vascular integrity that could enhance drug delivery and reduce tumor hypoxia.
    Keywords:  Autophagy; VCP/p97 inhibition; calcium signaling; cancer selectivity; organelle contact reorganization; proteostatic stress
    DOI:  https://doi.org/10.1080/15548627.2026.2677184
  29. Autophagy. 2026 May 20.
    A Rosella-PLIN2 knock-in mouse reveals lipophagy and immunometabolic interplay in atherosclerosis.
    Thomas Laval, Nathan Joyce, Dominique M Boucher, Honora Labrana, Valérie Rochon, Christina Emerton, Mishita Dharia, Sabrina Robichaud, Victoria Lorant, My-Anh Nguyen, Michèle Geoffrion, Katey J Rayner, Derrick Gibbings, Lauryl M J Nutter, Ryan C Russell, Mireille Ouimet.
      Cytosolic lipid droplets (LDs) regulate lipid homeostasis, with abnormal LD dynamics linked to metabolic diseases like atherosclerosis. In macrophage foam cells, LDs undergo autophagic degradation via lipophagy, but the extent of this process in vascular smooth muscle cell (VSMC) foam cells remains unclear. To track lipophagy in real time, we developed a Rosella-PLIN2 (perilipin 2) biosensor by tagging PLIN2 with the fluorescent pH-biosensor Rosella. We show that proatherogenic lipoproteins and autophagy activators stimulate lipophagy in human macrophages. Targeting LDs with an LC3 fusion protein or LD-autophagy tethering compounds (LD-ATTECs) selectively enhanced lipophagy, promoting foam cell LD clearance. In an atherosclerosis model, Rosella-PLIN2 accurately tracked lipophagy in arterial foam cells, revealing distinct PLIN2 expression patterns in macrophage and non-leukocyte foam cells. We identified a lipophagy deficiency in VSMC foam cells and demonstrate that enhancing lipophagy promotes LD catabolism in primary VSMC foam cells. TREM2+ macrophages exhibited high lipid content and low lipophagy flux, whereas TREM2- macrophages had low lipid content and high lipophagy flux. Our findings highlight a cell-specific interplay between lipophagy and immunometabolism in arterial foam cells, unveiling novel therapeutic avenues for atherosclerosis. Additionally, the Rosella-PLIN2 model provides a powerful tool for studying LD metabolism, offering new insights into lipid homeostasis and disease mechanisms.
    Keywords:  Atherosclerosis; autophagy; foam cells; lipid droplet; lipophagy; macrophages; reporter mouse; vascular smooth muscle cells
    DOI:  https://doi.org/10.1080/15548627.2026.2674711
  30. bioRxiv. 2026 May 07. pii: 2026.05.03.720925. [Epub ahead of print]
    Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
    Charles J Cho, Molly K Crowder, Amala K Rougeau, Thanh Nguyen, Steven J Bark, Sammy Lee, Jeffrey W Brown, Jason C Mills.
      The ability of epithelial cells to cope with injury and undergo regeneration depends on tightly coordinated cellular responses. IFRD1 is a stress-responsive protein that is evolutionarily conserved and required for the cellular regeneration program paligenosis; however, how IFRD1 works in paligenosis is not known. Here we demonstrate that IFRD1 is primarily a cytosolic ribosome-binding protein, specifically binding 80S monosomes that are not actively engaged in translation. Using multiple in vivo and in vitro injury models, including cerulein-induced pancreatitis in mice and tunicamycin-induced ER stress in cell culture, we demonstrate that IFRD1 acts as a ribosome-salvaging factor, preventing ribosomes from degradation. In the absence of IFRD1 during ER stress, non-translating 80S ribosomes were unstable and prone to disassembly and selective degradation. The resulting accumulation of degraded ribosomal subunits overwhelmed cellular autophagic machinery, as evidenced by accumulation of the autophagy-tagging protein p62, even though overall autophagic flux remained unaffected. Ultimately, cells lacking IFRD1 showed reduced mTORC1 activity followed by increased cell death, consistent with patterns observed in cells lacking IFRD1 during paligenosis. Thus, we detail a previously unrecognized cellular function for IFRD1 in stabilizing and preserving the mature ribosome pool during metabolic and translational transitions such as paligenosis.
    DOI:  https://doi.org/10.64898/2026.05.03.720925
  31. Autophagy. 2026 May 21.
    Cytosolic DNA as an inhibitor of rDNA transcription.
    Yinfeng Xu, Sheng Lu, Wei Wan.
      Cytosolic DNA is well established as an inducer of innate immunity through activating DNA-sensing machinery, such as the CGAS-STING1 pathway. Recently, we uncovered a previously unknown function of cytosolic DNA by elucidating its role in regulation of rDNA transcription. Cytosolic DNA interacts with UBTF and POLR1A, two essential components of the RNA polymerase I transcription machinery, thereby retaining a portion of these two proteins in the cytoplasm and resulting in an inhibition of rDNA transcription. This leads to decreased protein synthesis and reduced cell proliferation. Furthermore, STING1-induced autophagy selectively eliminates cytosolic DNA, abolishing the cytoplasmic retention of UBTF and POLR1A and consequently restoring rDNA transcription, protein synthesis, and cell proliferation. Thus, our findings reveal a DNA-sensing pathway-independent function of cytosolic DNA, which underscores cytosolic DNA as a novel player in cell metabolism.
    Keywords:  Autophagy; CGAS; STING1; cytosolic DNA; rDNA; rRNA
    DOI:  https://doi.org/10.1080/15548627.2026.2678428
  32. J Lipid Res. 2026 May 21. pii: S0022-2275(26)00090-8. [Epub ahead of print] 101064
    LPLAT7 Reutilizes Unsaturated 1-Lysophospholipids Formed During Lysosomal Phospholipid Degradation.
    Yang Xu, Sujith Rajan, Colin K L Phoon, Mindong Ren, M Mahmood Hussain, Michael Schlame.
      Lysosomal phospholipid degradation produces two types of metabolites, either 2-lysophospholipids with saturated fatty acids in sn-1 position or 1-lysophospholipids with unsaturated fatty acids in sn-2 position. They may either be degraded further or re-used for phospholipid synthesis. We found that LPLAT7 (LPGAT1), an acyltransferase of the endoplasmic reticulum, re-acylates specifically lysosome-derived 1-lysophospholipids that carry an unsaturated chain. The enzymatic activity of LPLAT7 was specific for stearoyl-CoA and 1-lyso-2-acyl positional isomers of unsaturated lysophospholipids. In Huh7 cells, Lplat7 knockout prevented the reacylation of 1-lysophospholipids generated by the lysosomal degradation of exogenous 2H-phosphatidylcholine. Inhibition of lysosomal phospholipid degradation reduced the abundance of 1-stearoyl-2-unsaturated PC in Huh7 cells. Lplat7 knockout blunted the loss of unsaturated lysophosphatidylcholine (LPC) in response to lysosomal inhibition, suggesting that LPLAT7 consumes unsaturated LPC formed by lysosomes. In mice, Lplat7 knockout increased the concentration of unsaturated lysophospholipids, reduced the abundance of 1-stearoyl-2-unsaturated species of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, and inhibited the regeneration of cellular membranes. It also triggered the accumulation of triglycerides, confirming earlier reports that unsaturated lysophospholipids induce lipid droplet formation. Thus, by re-acylating unsaturated 1-lysophospholipids, LPLAT7 shifts lipid metabolism from the biogenesis of lipid droplets to the biogenesis of membranes.
    Keywords:  Lipidomics; lysophospholipid; phospholipase A; phospholipid/biosynthesis; phospholipid/metabolism
    DOI:  https://doi.org/10.1016/j.jlr.2026.101064
  33. Cardiovasc Diagn Ther. 2026 Apr 24. 16(2): 35
    Mitophagy in cardiovascular diseases: a literature review.
    Ran Zhang, Junyan Zhang, Shuangliang Ma, Li Rao, Zhongxiu Chen.
       Background and Objective: Mitochondria generate nearly 90% of cellular adenosine triphosphate (ATP) and are essential for maintaining cardiac energetic homeostasis. Mitophagy, a selective autophagic process that removes damaged mitochondria, is critical for preserving mitochondrial quality and ensuring cardiomyocyte survival under stress. Given that cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are profoundly influenced by mitochondrial dysfunction, understanding mitophagy has become increasingly important. This review aims to summarize the current mechanistic findings related to mitophagy, examine its roles across major CVDs, and evaluate emerging mitophagy-targeted interventions with potential clinical application.
    Methods: A comprehensive literature search of PubMed was conducted using keywords, including "mitophagy", "cardiovascular disease", "myocardial ischemia-reperfusion", to retrieve relevant studies published in English between January 2020 and March 2025. Original studies, reviews, and clinically relevant reports were included in the literature review to ensure broad coverage of mechanistic and translational findings.
    Key Content and Findings: The review synthesizes current knowledge on canonical and noncanonical mitophagy pathways, as well as their roles in myocardial ischemia-reperfusion injury, heart failure, cardiomyopathies, and metabolic cardiomyopathy. Recent evidence highlights the dual nature of mitophagy, where both insufficient and excessive activation impair cardiac function. The review further discusses innovative therapeutic strategies, including mitochondrial-targeted nanoparticles, small-molecule mitophagy activators, and exercise-induced mitochondrial remodeling, along with their potential benefits and limitations. Key knowledge gaps have been identified, including the tissue-specific regulation of mitophagy and uncertainties surrounding dose-dependent therapeutic activation.
    Conclusions: Mitophagy is a pivotal determinant of mitochondrial homeostasis and cardiac health. While emerging interventions show promise, precise modulation remains challenging. Advancing quantitative assessment tools, defining safe activation thresholds, and developing cell-type-specific targeting strategies will be essential for clinical translation. This review provides a comprehensive framework that may guide future research and inform the development of mitophagy-based therapies for CVDs.
    Keywords:  Mitochondria quality control; cardiovascular diseases (CVDs); mitophagy; mitophagy-targeted therapy
    DOI:  https://doi.org/10.21037/cdt-2025-438
  34. Autophagy. 2026 May 18.
    Thr308-dephosphorylated AKT1 licenses SQSTM1-LC3C-Mediated antiviral autophagy.
    Zeyuan Hu, Lulu Lin, Yalan Zhong, Chunyan Li, Yahui Li, Haichong Wu, Jiyong Zhou, Boli Hu.
      AKT1 is classically known as a serine/threonine kinase controlling cell survival and proliferation, yet its kinase-independent functions remain poorly understood. Here we show that recognition of dsRNA viral capsids by membrane-associated HSP90AA1 disrupts the HSP90-AKT1 interaction, inducing AKT1 dephosphorylation at Thr308. This non-phosphorylated AKT1 acts as a scaffold to recruit PDPK1 and SQSTM1, enabling PDPK1-dependent phosphorylation of SQSTM1 at Ser349 and selective loading of viral capsids into LC3C-positive phagophores for degradation. An IBDV capsid mutant defective in SQSTM1 binding escapes this pathway. In vivo, expression of non-phosphorylatable AKT1 suppresses rotavirus replication in a SQSTM1-dependent manner. These findings identify an HSP90-initiated, kinase-independent AKT1 signaling axis that licenses antiviral macroautophagy/autophagy.
    Keywords:  AKT1; ATG8 family; LC3C; SQSTM1; dsRNA virus
    DOI:  https://doi.org/10.1080/15548627.2026.2677195
  35. Cell Rep. 2026 May 21. pii: S2211-1247(26)00442-0. [Epub ahead of print]45(6): 117364
    Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.
    Michel Fricke, Anna Mechel, Lennart Evers, Björn Twellsieck, Jessica M Grein, Maria-Sol Cima-Omori, Mohammed Al-Azzani, Tiago F Outeiro, Markus Zweckstetter, Erika L F Holzbaur, C Alexander Boecker.
      Parkinson disease (PD)-associated mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. Here, we show that knockout of the LRRK2-counteracting RAB phosphatase PPM1H causes a gene-dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in PD pathophysiology. Defective autophagosome transport and impaired aSyn degradation correlate with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that is dependent on LRRK2 kinase activity. These findings mechanistically link LRRK2-mediated RAB hyperphosphorylation to defective autophagosomal degradation and enhanced aggregation of aSyn, positioning the LRRK2-RAB axis as a key driver of PD pathophysiology.
    Keywords:  CP: Cell biology; CP: Neuroscience; LRRK2; PPM1H; RAB GTPases; alpha-synuclein; autophagy; axonal transport
    DOI:  https://doi.org/10.1016/j.celrep.2026.117364
  36. Cureus. 2026 May;18(5): e109147
    Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.
    Ngo Cheung.
      Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.
    Keywords:  als–ftd spectrum; amyotrophic lateral sclerosis; autophagy; microglial pruning; mitochondrial dysfunction; nad+; precision neurology; synaptic plasticity
    DOI:  https://doi.org/10.7759/cureus.109147
  37. Autophagy. 2026 May 17.
    PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage.
    Tingting Fu, Yanglin Wu, Bo Wang, Qin Zhang, Lujun Guo, Zezhang Han, Jia Cao, Jun Lin.
      Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical studies indicatethat specific hypoglycemic agents alleviate the symptoms of RA, while the potentialmolecular mechanism remains unknown. Herein, we initially assess the efficacyof various categories of anti-diabetic medications including biguanides, GLP1R(glucagon like peptide 1 receptor) agonists, SLC5A2/SGLT2 (solute carrierfamily 5 member 2) inhibitors, DPP4 (dipeptidyl peptidase 4) inhibitors,sulfonylureas, thiazolidinediones, and insulin analog in RA models ofcollagen-induced arthritis (CIA) and serum-transfer arthritis (STA). Resultsdemonstrate that solely thiazolidinediones (pioglitazone [PIOG]) confersuperior efficacy, whereas the other anti-diabetic agents provide minimal or notherapeutic benefits. Mechanistically, thiazolidinediones (PIOG) activatesPPARG/PPARγ (peroxisome proliferator activated receptor gamma) to promotemitophagic flux, thereby inhibiting aberrant NLRP3 inflammasome activation andreducing pro-inflammatory factors IL1B/IL1-BETA (interleukin 1 beta) and IL18 (interleukin18) release. Notably, loss of autophagy either genetically or pharmacologicallysubstantially diminishes the anti-inflammatory effects of PIOG both in vitroand in vivo. In summary, these results offer new mechanistic insight intodisease crosstalk and support the translational value of thiazolidinedionesPIOG as a candidate for precision therapy in RA or multimorbidity of RA and type2 diabetes mellitus (T2DM).
    Keywords:  Antidiabetic drug; NLRP3 inflammasome; PPARG; bone erosion; mitophagy; pioglitazone; rheumatoid arthritis; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1080/15548627.2026.2676071
  38. Int Immunopharmacol. 2026 May 20. pii: S1567-5769(26)00701-0. [Epub ahead of print]183 116855
    Deficiency of LAMP2A in macrophages accelerates hypoxia-induced atherosclerosis by inhibiting BNIP3-mediated mitophagy.
    Ning Wang, Zhiyuan Wang, Pinpeng Xie, Weichun Zhu, Zehao Chen, Jieqiong Peng, Longjin Xu, Dan Xu, Kang Fu, Wentao Chen, Chungang Zhai, Wenqiang Chen, Lei Qiao.
      Chaperone-mediated autophagy (CMA) is a critical biological process responsible for degrading proteins in lysosomes. Our previous studies demonstrated that impaired CMA in macrophages accelerated atherosclerosis under normoxic conditions. Hypoxia is an independent risk factor for atherosclerosis, and the role of CMA in atherosclerosis under hypoxic conditions is not clear. In this study, we generated myeloid-specific LAMP2A-knockout mice and LAMP2A-deficient THP-1 macrophage cells to investigate the role of CMA in hypoxia-induced atherosclerosis. We found that the expression of LAMP2A, the rate-limiting component of CMA, was increased in peripheral blood mononuclear cells (PBMCs) from patients with obstructive sleep apnoea syndrome (OSAS) and in atherosclerotic plaques of ApoE-/- mice exposed to hypoxic conditions. Furthermore, knockout of LAMP2A in macrophages promoted the development of atherosclerosis in vivo under hypoxic conditions, along with an obvious impairment of mitophagy in atherosclerotic plaques and in LAMP2A-deficient THP-1 macrophages. Mechanistically, LAMP2A deficiency impaired mitophagy by inhibiting the expression of NIX/BCL2-interacting protein 3 (BNIP3) via miR-134-5p, while upregulation of BNIP3 restored mitophagy function in LAMP2A-deficient macrophages. In conclusion, our study demonstrated that deficiency of LAMP2A in macrophages accelerated hypoxia-induced atherosclerosis, partially through the inhibition of BNIP3-mediated mitophagy via miR-134-5p.
    Keywords:  Atherosclerosis; BNIP3; Chaperone-mediated autophagy; Hypoxia; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2026.116855
  39. Cell Death Dis. 2026 May 17.
    VCP modulation ameliorates pathological features in C9orf72 models.
    Veronica Ferrari, Barbara Tedesco, Marta Cozzi, Paola Pramaggiore, Maria Cristina Gagliani, Rocio Magdalena, Laura Cornaggia, Elena Casarotto, Marta Chierichetti, Ali Mohamed, Maria Brodnanovà, Carmelo Milioto, Margherita Piccolella, Mariarita Galbiati, Valeria Crippa, Alessandro Provenzani, Katia Cortese, Paola Rusmini, Riccardo Cristofani, Angelo Poletti.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-08856-1
  40. bioRxiv. 2026 May 13. pii: 2026.05.06.723260. [Epub ahead of print]
    Unexpected ribosome turnover during prolonged translation inhibition.
    Paul J Russell, Caleb A Clark, Mia Ashriem, Michael G Kearse.
      Eukaryotes use several distinct quality control pathways to resolve aberrant ribosomes and mRNAs. For example, the no-go decay mRNA pathway is stimulated after ribosome collisions caused by stalled ribosomes translating damaged or truncated mRNAs. Separate decay pathways for non-functional 40S and 60S subunits containing rRNA mutations affecting decoding and peptidyl transferase activity, respectively, have also been elucidated. To our knowledge, whether eukaryotes have evolved a quality control pathway to sense and process globally stalled ribosomes is unclear; however, such a pathway would be advantageous to eukaryotes during exposure to natural elongation inhibitors such as ricin and diphtheria toxin. Here, we test how prolonged robust inhibition of elongation using a high dose of cycloheximide (CHX) affects ribosome turnover. Despite no decrease in cell viability and that mammalian ribosomes have been classically characterized of having a half-life of 3-5 days, a single 24 hr high dose of CHX resulted in drastically shortened half-lives (<24 hr) of 28S and 18S rRNA in A549 cells. A ~2-fold reduction in nearly all ribosome species was observed by polysome analysis in HeLa and A549 cells after prolonged CHX treatment. Depletion of ribosomes was also evident when assessing ribosomal proteins from both the 40S and 60S subunits by Western blot. Literature supports that ribosomes can be degraded by autophagy and the ubiquitin (Ub)-proteasome system. Upon testing inhibitors of both pathways, only proteasome inhibitors (i.e., MG132 and bortezomib) rescued both rRNA and ribosomal protein levels. Proteasome inhibitors also rescued ribosome levels in polysome profiling experiments. Remarkably, rRNA levels were not rescued during CHX treatment when co-treated with the Ub activating enzyme E1 inhibitor, TAK243. Polysome analysis also showed that the high prolonged dose of CHX did not cause robust accumulation of collided ribosomes compared to control treatments. Proteasome-dependent turnover of rRNA was also observed with high doses of other elongation inhibitors, namely anisomycin, homoharringtonine, and lactimidomycin. The recognition capabilities of the pathway were further expanded as we observed that 80S ribosomes not trapped on the mRNA were also targeted for degradation by the proteasome. Together, our findings define the framework of a regulatory pathway in mammalian cells that degrades both ribosomal subunits in response to prolonged periods of robust elongation inhibition.
    DOI:  https://doi.org/10.64898/2026.05.06.723260
  41. Nat Commun. 2026 May 19.
    Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.
    Junyu He, Meiqi Chen, Laiqin Peng, Qiqiong Wang, Yizhuang Lu, Yimin Chen, Xinyao Li, Yanling Mou, Jianjun Wang, Yuxiong Guo, Kai Wu, Yumei He.
      Group 3 innate lymphoid cells (ILC3) are crucial in neonatal necrotizing enterocolitis (NEC); however, the underlying mechanisms remain elusive. Here, we identify NKp46⁻CCR6⁻ (double-negative, DN) ILC3s as the dominant pathogenic subset driving NEC via IL-17 A secretion, which disrupts intestinal barrier integrity. Mechanistically, Atg5 activates autophagy in DN ILC3s during NEC. Atg5 conditional knockout in RORγt⁺ cells mitigates NEC, reduces DN ILC3 accumulation and IL-17 A production. Atg5 deficiency also decreases HIF-1α chromatin accessibility and transcriptional activity, shifting DN ILC3 metabolism from glycolysis to fatty acid oxidation. Lipidomics reveals phosphatidylcholine as a key downstream metabolite of Atg5-mediated autophagy. Phosphatidylcholine supplementation suppresses DN ILC3-driven inflammation, restores metabolic homeostasis, elevates Clostridium abundance, and ameliorates NEC in mice. Importantly, human NEC tissues exhibit increased ILC3 proportions, autophagic activity, and IL-17 A/IL-22 secretion. Thus, we uncover an Atg5-autophagy-glycolipid metabolic axis in DN ILC3s that drives NEC pathogenesis, providing a promising therapeutic target for neonatal NEC.
    DOI:  https://doi.org/10.1038/s41467-026-73356-x
  42. Brain Dev. 2026 May 17. pii: S0387-7604(26)00048-3. [Epub ahead of print]48(3): 104547
    Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.
    Junxia Li, Qing Zhao, Hongyan He, Xueqin Song.
       OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe hereditary disorder characterized by dystrophin deficiency, leading to progressive muscle weakness. Mitochondrial dysfunction and impaired quality control, particularly via the PTEN-induced putative kinase 1 (PINK1)-E3 ubiquitin ligase PARK2 (PARKIN) mitophagy pathway, are implicated in DMD pathogenesis, but the impact of exercise remains unclear. This study investigated the effects of short-term high-intensity exercise on skeletal muscle pathology and mitophagy in mdx mice.
    METHODS: Skeletal muscle from DMD patients and non-dystrophic controls (CTR) was analyzed for mitochondrial content and PINK1-PARKIN expression. Eight-week-old male mdx and C57 control mice underwent a 5-day rotarod exercise protocol. Muscle pathology was assessed using hematoxylin and eosin (HE), acid phosphatase (ACP), and succinate dehydrogenase (SDH) staining. Mitophagy was evaluated via immunofluorescence for microtubule-associated protein 1 light chain 3 (LC3), cytochrome c oxidase subunit IV (COXIV), and voltage-dependent anion channel (VDAC), as well as western blotting for PINK1 and PARKIN. Transmission electron microscopy (TEM) was used to visualize mitochondrial ultrastructure.
    RESULTS: In DMD patients, skeletal muscle showed reduced mitochondrial content and dysregulated PINK1-PARKIN expression. In mdx mice, basal mitophagy markers were elevated. Short-term high-intensity exercise exacerbated muscle necrosis and inflammation in mdx mice while impairing the activation of PINK1-PARKIN-mediated mitophagy, contrasting with the adaptive response in wild-type mice.
    CONCLUSION: Short-term high-intensity exercise exacerbates skeletal muscle pathology in mdx mice, which is associated with impaired activation of PINK1-PARKIN-mediated mitophagy, underscoring the critical role of mitochondrial quality control in DMD and the need for tailored exercise regimens.
    Keywords:  Duchenne muscular dystrophy; Exercise; Mitophagy; Muscle injury; PINK1-PARKIN pathway
    DOI:  https://doi.org/10.1016/j.braindev.2026.104547
  43. EMBO J. 2026 May 20.
    Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.
    Sabrina Chumpen Ramirez, Dmitry Shvarev, Prado Vargas Duarte, Yara Ahmed, Jana Milach, Emma Lang, Stefan Kuchenbuch, Stefano Vanni, Fulvio Reggiori, Arne Moeller, Christian Ungermann.
      During macroautophagy, the de novo formation of the autophagosome at a membrane contact site (MCS) with the endoplasmic reticulum requires directional lipid flux for the growth of the initial phagophore before its sealing into an autophagosome and subsequent fusion with the lysosome/vacuole. It remains unclear, however, how the formation of this specialized MCS and the directionality of the lipid flux are controlled. Here, we present the structure of the key lipid transfer protein Atg2 from yeast solved together with its Atg18 binding partner, a phosphatidylinositol-3-phosphate (PtdIns3P) effector, using cryo-electron microscopy. We reveal a new interface in Atg2 that, together with PtdIns3P, is required for Atg18 recruitment and lipid transfer activity. Furthermore, we visualize lipid densities along the internal hydrophobic cavity of Atg2, providing structural evidence that Atg2 cavity is filled with lipids throughout the entire length, even when Atg2 is cytosolic. Finally, molecular dynamics simulations show that the complex generates membrane curvature, efficiently positioning the lipid channel of Atg2 towards the membrane to promote lipid transfer into the elongating phagophore.
    DOI:  https://doi.org/10.1038/s44318-026-00802-3
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