bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–05–17
fifty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. TBK1 restricts IRGQ-mediated autophagy.
  2. mTOR-Dependent Autophagy Is Conserved in the Ciliate Tetrahymena thermophila.
  3. Atg7-Atg12 conjugation and autophagy are negatively regulated by the disordered region of Atg12.
  4. Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
  5. Identification of small-molecule autophagy activators via GFP-LC3 high-throughput screening and a cargo-based autophagy flux and processing assay.
  6. Regulation of survival, growth, and metabolism by neuronal mTOR.
  7. A dual phospholipase system instructs membrane hydrolysis during the final stages of plant autophagy.
  8. A role for CASM in the repair of damaged Golgi architecture.
  9. S-palmitoylation of ATG4B facilitates the deconjugation of LC3-II to promote autophagy.
  10. Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes.
  11. Integrated clinical and computational data-based repurposing of econazole as a novel autophagic activator in ULK1-related Parkinson disease.
  12. Autophagy and metabolic homeostasis: Exploration in obesity‑related metabolic diseases (Review).
  13. mTOR signaling regulates morphogenesis and differentiation during lacrimal gland development.
  14. Stub1 promotes chaperone-mediated autophagy to suppress antiviral immunity.
  15. mTOR-NAA10-C7orf50 axis senses nutritional status to coordinate ribosome biogenesis and autophagy.
  16. Selective autophagy in kidney health and disease.
  17. Understanding Dysfunctional Autophagy and Mitophagy in Inflammatory Cardiovascular Disease.
  18. Methods for Autophagy Detection by Fluorescence Microscopy.
  19. Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.
  20. A review of autophagy in the pancreas: normal physiology and pathophysiology.
  21. Formation and function of a novel Atg21-retromer complex in S. cerevisiae.
  22. Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
  23. Mechanisms of Action of FUNDC1 in Cerebral Ischemia-Reperfusion Injury.
  24. Small CD63 + CD81+ extracellular vesicles induce autophagy via the FOXO3a pathway in pancreatic cancer cells during starvation.
  25. Intracellular lipopolysaccharide binds RETREG1/FAM134B to regulate ER remodeling upon bacterial infection.
  26. Autophagy-Neuroinflammation Axis in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.
  27. NBR1-Mediated Selective Autophagy in Plant Development and Stress Responses.
  28. BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.
  29. Bench to bedside: is rapamycin headed for the docTOR?
  30. PRKN-IMMT/MIC60 axis promotes myocardial ischemia-reperfusion injury via lysosomal degradation of GPX4.
  31. ER-driven Contact Sites in Autophagosome Biogenesis Sequence.
  32. Selective detection of lipophagy with a highly specific lipid droplet probe.
  33. Loss of macroautophagy results in abnormality of the endoplasmic reticulum in insulin-secreting MIN6 cells.
  34. Mitophagy in ophthalmic pathologies: Molecular mechanisms and therapeutic implications.
  35. Fluorescence-On Imaging of Golgiphagy with a Golgi Apparatus-Specific Metabolic Lipid Labeling Probe Fluorogenic to Lysosomal Acidity.
  36. The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62.
  37. Zinc excess promotes lysosome remodeling by activating HLH-30/TFEB through the action of the high zinc sensor HIZR-1.
  38. AMPK: a master regulator of mitochondrial quality and quantity.
  39. Urolithin A: Potential to enhance autophagic clearance and mitigate neuroinflammation in Alzheimer's disease.
  40. The multifaceted regulation of autophagy protein ATG16L1 and its implications in human diseases.
  41. Tunnelling Nanotube-Mediated Lysosome Sharing Promotes Osteocyte Survival via Transcellular Autophagy.
  42. Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
  43. Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
  44. Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
  45. Implications of ferritinophagy in cardiovascular diseases and its pharmacological modulation: underlying mechanisms and clinical translation strategies.
  46. Proteasome inhibition enhances lysosome-mediated targeted protein degradation.
  47. A TerminaTOR of mTORC1 signaling.
  48. The modifier matrix: emerging roles of ubiquitin-like proteins in Alzheimer's disease.
  49. The dual function of mitophagy in ferroptosis.
  50. TIM-3-dependent lysosome biogenesis is required for myelin debris clearance in macrophages.
  51. Hypoxia-induced autophagic degradation of HIF-1α attenuates cellular aging and extends mammalian lifespan.
  1. Nat Commun. 2026 May 13. pii: 4335. [Epub ahead of print]17(1):
    TBK1 restricts IRGQ-mediated autophagy.
    Uxia Gestal-Mato, Pauline Lascaux, Sergio Alejandro Poveda-Cuevas, Alberto Cristiani, Belinda Camp, Mahyar Aghapour, Aparna Viswanathan Ammanath, Ramachandra M Bhaskara, Ivan Dikic, Lina Herhaus.
      The autophagy-lysosome system directs the degradation of a wide variety of cytoplasmic cargo such as damaged organelles, protein aggregates, and invading pathogens. The autophagy receptor IRGQ harbors two distinct LIR domains, with LIR1 exhibiting high selectivity for GABARAPL2. Proteomic, biochemical, and high-throughput microscopy studies reveal that the IRGQ-GABARAPL2 complex functions as a hub for the interaction between hATG8s and the autophagy initiation machinery, promoting their lipidation and overall autophagic flux. The interaction of IRGQ with GABARAPL2 is regulated via TBK1. Upon TBK1 activation, GABARAPL2 is phosphorylated on S10, which disrupts IRGQ-GABARAPL2 complexation and therefore its interaction with the autophagy initiation machinery, resulting in a reduction of the autophagic flux of GABARAPL2 and IRGQ-cargo, without affecting bulk autophagy. These findings broaden IRGQ's role in autophagy, identifying it as an interaction hub for autophagy initiation that is negatively regulated by TBK1.
    DOI:  https://doi.org/10.1038/s41467-026-73005-3
  2. J Eukaryot Microbiol. 2026 May-Jun;73(3):73(3): e70086
    mTOR-Dependent Autophagy Is Conserved in the Ciliate Tetrahymena thermophila.
    Shinya Matsuda, Kentaro Nakano.
      In Tetrahymena, autophagy appears to be involved in the integrity of the mitochondria which supply energy for active ciliary movement on the cell surface, the maintenance of various structures such as cilia, and cell shape changes associated with starvation. In this organism, which is evolutionarily distant from yeast and animal cells, the mechanisms controlling autophagy remain largely unknown. mTOR is a major regulatory factor that suppresses autophagy induction when cells are under nutrient-rich conditions. Previous studies suggest that T. thermophila contains two mTOR orthologs, but lacks the canonical TORC1 subunits, while retaining TORC2-associated components. To determine whether mTOR controls autophagy in T. thermophila, we examined Torin1, an ATP-competitive inhibitor that blocks mTOR kinase activity regardless of complex composition. It markedly triggered ATG8 puncta formation and mitochondrial degradation under nutrient-rich conditions. In contrast, rapamycin, a TORC1-specific inhibitor widely used to induce autophagy, did not affect cell growth or autophagy. These findings demonstrate that mTOR functions as a negative regulator of autophagy in T. thermophila, likely through a rapamycin-insensitive TORC2 or noncanonical complex. Our results highlight lineage-specific divergence in mTOR signaling architecture and expand our understanding of the diversity of autophagy regulation across eukaryotes.
    Keywords:   Tetrahymena ; Torin1; autophagy; mTOR
    DOI:  https://doi.org/10.1111/jeu.70086
  3. Commun Biol. 2026 May 15.
    Atg7-Atg12 conjugation and autophagy are negatively regulated by the disordered region of Atg12.
    Hana Popelka, Daniel J Klionsky.
      The macroautophagy/autophagy machinery has two ubiquitin-like (UBL) conjugation systems. The Atg8/MAP1LC3/GABARAP (yeast/human) and Atg12/ATG12 proteins are UBL substrates for Atg7/ATG7, a non-canonical E1 enzyme, that thioesterifies its substrates; however, autophagy requires a much greater amount of conjugated Atg8 (Atg8-PE) than Atg12 (Atg12-Atg5). Exactly how Atg7/ATG7 distinguishes between its two substrates to facilitate this differential biogenesis remains elusive. Here, analyses of recombinant complexes of yeast proteins reveal that the N termini of Atg8 and Atg12 are structural determinants for conjugation to Atg7, but play no role in conjugation to Atg3 or Atg10, non-canonical E2 enzymes. The disordered N terminus of Atg12 is a protector of the Atg12 C terminus and a negative regulator of Atg7-Atg12 conjugation and autophagy, whereas the N-terminal helical domain in Atg8 promotes autophagy and has a high avidity to Atg7. We show that balanced autophagy requires different specific N termini attached to the UBL domains, which are structural determinants for selective transfer to the native E2s. These findings deepen our understanding of the two autophagy UBL conjugation systems that is far from complete.
    DOI:  https://doi.org/10.1038/s42003-026-10269-x
  4. Nat Chem Biol. 2026 May 14.
    Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
    Yanghao Zhong, Ayse Z Sahan, Zhengyao Shao, Qian-Yi Zhang, Xin Zhou, Jack G Haggett, Keiichi Koshizuka, Samuel A Myers, J Silvio Gutkind, Jin Zhang.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient sensor that integrates diverse inputs to regulate protein translation and cell growth. While mTORC1 is activated on the lysosome in the classical model, it has become increasingly clear that this multifaceted signaling complex is active at various subcellular locations, such as the nucleus. However, what specific functions mTORC1 serves at these locations and how its signaling is compartmentalized are unclear. To interrogate subcellular pools of mTORC1, we developed TerminaTOR, a genetically encodable inhibitor of mTORC1 that can be targeted to specific subcellular locations. When TerminaTOR is directed to the lysosome, it inhibits canonical lysosomal mTORC1 and induces autophagy. Furthermore, TerminaTOR targeted to the nucleus specifically inhibits nuclear mTORC1, uncovering noncanonical roles of nuclear mTORC1 in regulating the transcription of CCAAT motif-containing genes. Thus, mTORC1 exhibits functional spatial compartmentalization and TerminaTOR serves as a powerful tool for unraveling spatially regulated functions of mTORC1 across different scales.
    DOI:  https://doi.org/10.1038/s41589-026-02188-z
  5. Eur J Pharmacol. 2026 May 09. pii: S0014-2999(26)00440-1. [Epub ahead of print]1026 178958
    Identification of small-molecule autophagy activators via GFP-LC3 high-throughput screening and a cargo-based autophagy flux and processing assay.
    Freke Mertens, Farnaz Sedigheh Takhsha, Mélissa Lallier, Nikolai Engedal, Vera Goossens, Dominique Audenaert, Pieter-Jan Guns, Lynn Roth, Peter Vandenabeele, Erik Fransen, Cécile Vindis, Pieter Van der Veken, Vincent Timmerman, Guido R Y De Meyer, Wim Martinet.
       BACKGROUND AND AIM: Autophagy maintains cellular homeostasis by recycling macromolecules and nutrients. It involves the sequestration of superfluous or damaged cellular components into autophagosomes, which fuse with lysosomes for degradation. Reduced autophagy is implicated in numerous diseases, which may be treatable with autophagy-inducing drugs. However, most clinically available inducers act through mTORC1 inhibition, causing off-target effects that limit their therapeutic use. This study aimed to identify novel autophagy-inducing compounds that act independently of mTORC1, thereby offering greater translational potential.
    METHODS: A high-throughput imaging assay was optimised to quantify autophagosome-like structures in L929 fibroblasts expressing GFP-LC3, a fluorescent autophagosome membrane marker. Hits were validated alongside several reference autophagy modulators in retinal epithelial hTERT RPE-1 cells expressing the LDHB-mKeima autophagy cargo reporter. This assay distinguishes functional autophagy flux inducers from compounds that merely increase autophagosome accumulation by blocking late-stage autophagy. Western blotting was used to investigate the mechanism of autophagy initiation.
    RESULTS: High-throughput screening identified 30 hits that increased autophagosome-like structures more than fourfold. Ten compounds were confirmed to induce autophagic flux of bulk cargo. Nine of these acted independently of mTORC1, while elevating autophagic flux to a similar extent as the mTORC1 inhibitor rapamycin.
    CONCLUSION: While GFP-LC3-based assays enabled efficient high-throughput screening, incorporation of the LDHB-mKeima cargo-based assay was essential for identifying functional autophagy flux activators. Nine compounds were identified that promoted autophagic cargo flux via mTORC1-independent mechanisms, providing promising leads for discovering new molecular targets and developing safer, more effective autophagy-based interventions to treat human disease.
    Keywords:  Autophagic cargo flux; Autophagy; GFP-LC3; High-throughput screening; LHDB-mKeima
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178958
  6. Geroscience. 2026 May 12.
    Regulation of survival, growth, and metabolism by neuronal mTOR.
    Stacy A Hussong, Raquel Burbank Roberts, Jonathan J Halloran, Stephen F Hernandez, Candice E Van Skike, Angela O Dorigatti, Nicholas DeRosa, Michael E Walsh, Vanessa Y Soto, Daniel A Pulliam, Holly Van Remmen, Steven N Austad, Veronica Galvan.
      Reducing activity of the mechanistic/mammalian target of rapamycin (mTOR) with rapamycin extends lifespan and healthspan in many species. The mechanisms by which mTOR regulates lifespan and healthspan, however, are still unknown. Understanding how mTOR signaling in different cell types regulates lifespan and aspects of healthspan is urgently needed if we are to harness the potential individual and societal benefits of healthspan extension by mTOR attenuation. mTOR kinase can form two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The regulatory associated protein of mTOR (Raptor) is required for the assembly of mTORC1, the primary target of rapamycin. To define the role of mTORC1 and mTORC2 signaling during development in the regulation of healthspan we either ablated or reduced expression of Rptor (Raptor) or Mtor (mTOR) in neurons of mice. Developmental knock-down of Mtor (mTORKD) exclusively in neurons, had no significant impact on embryonic survival, but significantly increased adult mortality. In contrast, neuronal knockdown of Rptor (RaptorKD) during development reduced embryonic viability, but did not appear to impact adult survival, suggesting that reducing mTORC1 may confer a survival advantage after birth. Reduction of either Rptor or Mtor (mTORKD, RaptorKD) during development, however, significantly decreased growth rates, body weight, fat mass, resting and fasting blood glucose, and exercise capacity. Taken together, our studies indicate that neuronal mTORC1 plays a critical role in the determination of body size during development, as well as fat mass, metabolic states and exercise capacity during adulthood.
    Keywords:  Aging; Metabolism; Neuron; mTOR
    DOI:  https://doi.org/10.1007/s11357-026-02294-9
  7. Nat Commun. 2026 May 14.
    A dual phospholipase system instructs membrane hydrolysis during the final stages of plant autophagy.
    Julie Castets, Matthieu Buridan, Inés Toboso Moreno, Valérie Wattelet-Boyer, Víctor Sánchez de Medina Hernández, Rodrigo Enrique Gomez, Franziska Dittrich-Domergue, Josselin Lupette, Clément Chambaud, Stéphanie Pascal, Tarhan Ibrahim, Tolga O Bozkurt, Yasin Dagdas, Frédéric Domergue, Jérôme Joubès, Elena A Minina, Amélie Bernard.
      Autophagy is a conserved intracellular catabolic process, critical for plant stress tolerance. Upon their delivery in the vacuole, how autophagic bodies containing cargo are hydrolyzed to warrant autophagy degradation remains unclear in multicellular organisms. Here, we found that two Arabidopsis phospholipases, LCAT4 and LCAT3, traffic to the vacuolar lumen and converge on autophagic bodies through fundamentally different routes. While LCAT4 directly binds ATG8 and uses autophagy as a transport system to reach the vacuole prepackaged within autophagosomes, LCAT3 traffics to the lytic compartment independently of autophagosome formation. Knocking out both genes causes an accumulation of autophagic bodies accompanied with a reduction in autophagy degradation. In vivo reconstitution demonstrated that LCAT3 can hydrolyse the membrane of autophagic bodies, enabling the activity of LCAT4 to enhance this process. Together, this work sheds light on the vacuolar stages of autophagy, showing that plants have evolved a multi-component pathway for the efficient disruption of autophagosomal membranes as a critical step for the completion of the autophagy pathway.
    DOI:  https://doi.org/10.1038/s41467-026-73116-x
  8. Autophagy. 2026 May 11.
    A role for CASM in the repair of damaged Golgi architecture.
    Seeun Oh, Saif Ullah, Bhaskar Saha, Michael A Mandell.
      The term CASM describes a process in which MAP1LC3B/LC3B and other Atg8-family proteins are covalently ligated to lipids in damaged endomembranes. While CASM is commonly described as a cytoprotective response to multiple types of membrane damage, how CASM helps cells maintain homeostasis is still unclear. Here, we show that CASM maintains Golgi apparatus architecture following the loss of TRIM46, a ubiquitin ligase with roles in microtubule organization. TRIM46 deficient cells were notable for enhanced TFEB-driven lysosomal biogenesis and Golgi ribbon fragmentation, with colocalization of the trans-Golgi marker TGOLN2 and the Atg8-family proteins LC3B and GABARAP. Further studies revealed that the Golgi Atg8ylation seen in TRIM46 knockout cells was not degradative and mechanistically resembled CASM. Genetic inhibition of CASM in TRIM46 deficient cells reduced TFEB activation and exacerbated the Golgi morphology defects, suggesting that CASM contributes to Golgi repair. Accordingly, Golgi reformation after drug-induced fragmentation was impaired upon knockdown of CASM genes. Together, these studies identify lysosomal biogenesis and CASM as coordinated features of a Golgi damage response, with CASM acting to preserve Golgi integrity.
    Keywords:  Atg8ylation; CASM; TFEB; TRIM46; VAIL; autophagy; golgi damage/golgi fragmentation; lysosomal biogenesis; microtubule; tripartite motif
    DOI:  https://doi.org/10.1080/15548627.2026.2673560
  9. Autophagy. 2026 May 10.
    S-palmitoylation of ATG4B facilitates the deconjugation of LC3-II to promote autophagy.
    Jiaxin Wang, Huini Zeng, Wenyan Wu, Jia Yao, Yu Wang, Jiayue Han, Weiyin Zou, Shangze Li, Aimin Yang.
      Macroautophagy/autophagy plays a critical role in maintaining cellular homeostasis. A defining characteristic of autophagy is the formation of the autophagosomes, which is regulated by a series of ATG (autophagy related) proteins. ATG4B serves as a pivotal protein responsible for the cleavage of the precursor form of MAP1LC3/LC3 and the deconjugation of LC3-II, which is a prerequisite for the formation and expansion of phagophores, the precursors to autophagosomes. In the present study, we demonstrated that ATG4B undergoes S-palmitoylation, in which palmitic acid is attached to the side chain of a cysteine residue. S-palmitoylation of ATG4B is catalyzed by ZDHHC9 (zDHHC palmitoyltransferase 9), and reversed by ABHD17B (abhydrolase domain containing 17B, depalmitoylase). Interestingly, S-palmitoylation of ATG4B at Cys89 is crucial for LC3-II deconjugation in vitro and in vivo, but not for proLC3 cleavage. In conclusion, our study reveals a crucial role of ATG4B S-palmitoylation in the deconjugation of LC3-II in autophagy.
    Keywords:  ABHD17B; ATG4B; LC3-II deconjugation; S; ZDHHC9; autophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2672699
  10. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2527503123
    Chaperone-mediated autophagy protects against retinal photoreceptor degeneration by modulating proteostasis of glucose metabolism enzymes.
    Raquel Gómez-Sintes, Inmaculada Tasset, Ignacio Ramírez-Pardo, Adrián Martín-Segura, Sandra Alonso-Gil, Antonio Díaz, Kristen Lindenau, Concepción Lillo, Pedro de la Villa, Simone Sidoli, Evripidis Gavathiotis, Ana María Cuervo, Patricia Boya.
      Defective proteostasis is a hallmark of aging cells and tissues. Among the different components of the proteostasis network, in this study, we focus on a selective form of autophagy known as chaperone-mediated autophagy (CMA), and we set out to understand its physiological role in the retina. Using mice deficient for CMA [knockout for lysosome-associated membrane protein type 2A (Lamp2A)], we have found that CMA blockade leads to impaired visual function, altered retinal proteostasis, and photoreceptor cell death. Conversely, mice that overexpress human LAMP2A show higher resistance to chemically induced photoreceptor degeneration and slower visual function decline. We found a similar protective effect against retinal degeneration upon pharmacological activation of CMA. To start elucidating the mechanisms behind CMA's protective role in the retina, we used comparative proteomics and found elevated levels of enzymes related with glucose metabolism in CMA-deficient retinas that phenocopy those observed in old mice retinas. Overall, our results highlight a cytoprotective role for CMA in retina, in part through proteostatic regulation of enzymes involved in glucose metabolism, and support the feasibility of pharmacologically upregulating CMA against retinal degeneration.
    Keywords:  aging; autophagy; metabolism; retina; small-molecules
    DOI:  https://doi.org/10.1073/pnas.2527503123
  11. Autophagy. 2026 May 11.
    Integrated clinical and computational data-based repurposing of econazole as a novel autophagic activator in ULK1-related Parkinson disease.
    Jin Zhang, Wenke Jin, Yuqi Fu, Yongqi Zhen, Yanmei Chen, Wei Liu, Wei Huang, Zhiwen Wang, Hong-Ping Zhu, Qian-Qian Yang, Gu Zhan, Qian Zhao, Cheng Peng, Lan Zhang, Bo Han, Bo Liu.
      Parkinson disease (PD), the second most common neurodegenerative disorder, is pathologically linked to dysregulated autophagy, a conserved lysosomal degradation pathway. Current conventional PD therapies are often limited by significant side effects, underscoring the demand for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to address this unmet clinical need. Here, by integrating clinical data analysis, we identified an association between autophagy impairment and specific PD patient subtypes, suggesting that ULK1-dependent autophagy activation may offer therapeutic benefit. Through systematic screening for autophagy induction and neuroprotective activity, we identified econazole, a known imidazole antifungal, as a promising candidate. Econazole exhibited robust therapeutic effects across multiple PD models, including MPTP-induced zebrafish and mouse models, as well as SNCAA53T mutant mouse models. Notably, its efficacy was dependent on functional autophagy, as autophagy inhibition abrogated its beneficial effects. Mechanistically, econazole activated ULK1, enhanced autolysosome formation, and promoted clearance of SNCA aggregates. Mouse brain microarray analysis indicated that econazole-activated ULK1 suppresses MAP3K12/DLK-MAPK8/JNK-MAPK9/JNK2-mediated neuronal apoptosis. Further phosphoproteomic profiling uncovered a novel ULK1-HSPA8/Hsc70 interaction that promotes LAMP1 and LAMP2 activation and enhances lysosomal function. This ULK1-HSPA8 complex additionally activated the BECN1 (beclin 1) complex to facilitate autophagosome formation. Together, our findings highlight a clinical data-guided drug repurposing approach that identifies econazole as a potent autophagy activator with therapeutic efficacy in ULK1-linked PD models, opening new avenues for PD treatment.
    Keywords:  Autophagy; HSPA8; MAP3K12; drug repurposing; lysosome
    DOI:  https://doi.org/10.1080/15548627.2026.2673173
  12. Int J Mol Med. 2026 Jul;pii: 190. [Epub ahead of print]58(1):
    Autophagy and metabolic homeostasis: Exploration in obesity‑related metabolic diseases (Review).
    Chenglin Lu, Xiangyu Qi, Yuting Tong, Peng Lu, Dandan Luo, Qingbo Guan, Chunxiao Yu.
      Autophagy is an evolutionarily conserved catabolic process in which excessive nutrients, toxic protein aggregates, damaged organelles, and invading microorganisms in the cytoplasm can be isolated by the double‑membrane structure of autophagosomes and delivered to lysosomes for degradation. Over the past two decades, research on autophagy has made significant progress. Autophagy not only plays a crucial role in maintaining intracellular homeostasis but also contributes to the development of various metabolic diseases. Metabolic imbalance of nutrients in obesity‑related metabolic diseases can interfere with the autophagy process through a variety of mechanisms, resulting in further aggravation of the pathological damage of related organs. However, under certain conditions, inhibition of autophagy can have beneficial effects, thereby alleviating some of the harmful consequences of obesity. In this review, we will focus on the latest advances in the study of autophagy in obesity‑related metabolic disorders, including type 2 diabetes, non‑alcoholic fatty liver disease, and atherosclerosis. We will systematically discuss the definition and types of autophagy, the regulation of autophagy by nutrients, the imbalance of autophagy in obesity‑related metabolic diseases and its molecular mechanism, and finally, we will summarize some drugs targeting the autophagy pathway.
    Keywords:  atherosclerosis; autophagy; diabetes; non‑alcoholic fatty liver disease; obesity‑related metabolic diseases
    DOI:  https://doi.org/10.3892/ijmm.2026.5861
  13. Biochem Biophys Res Commun. 2026 Jul 09. pii: S0006-291X(26)00667-4. [Epub ahead of print]821 153903
    mTOR signaling regulates morphogenesis and differentiation during lacrimal gland development.
    Manabu Sakai, Mahiro Murakami, Takayoshi Sakai.
      Various molecules are involved in the development of the lacrimal gland (LG), the role of the mammalian target of rapamycin (mTOR) signaling pathway, including mTORC1 and mTORC2, remains unclear. We first used an ex vivo LG organ culture system that closely mimics in vivo conditions to investigate the mTOR signaling-related proteins. To investigate the dynamics of mTOR signaling-related proteins during LG development, we employed an ex vivo LG organ culture system treated with pharmacological inhibitors, including rapamycin, LY294002, and compound C. In addition, to assess the involvement of mTOR signaling in vivo, rapamycin was administered to pregnant female ICR mice. In this study, we clarify for the first time that two pathways both mTORC1 and mTORC2 via PI3K, and mTOR signaling pathway via AMPK are related to LG development in ex vivo organ culture. In addition, we report that the rapamycin-treated mice exhibited decreased body weight and LG size. These findings suggest that the mTOR signaling pathway plays a crucial role in LG development both ex vivo and in vivo.
    Keywords:  Development; Lacrimal gland; Organ culture; mTOR
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153903
  14. Autophagy. 2026 May 11. 1-2
    Stub1 promotes chaperone-mediated autophagy to suppress antiviral immunity.
    Hongyang Liu, Li Huang, Changjiang Weng.
      The E3 ubiquitin ligase Stub1 (CHIP) is a core regulator of protein homeostasis and antiviral innate immunity, with established roles in targeting RIG‑I and MAVS for proteasomal or autophagic degradation. Here, we summarize our recent work revealing that Stub1 negatively regulates type I interferon (IFN‑I) production by driving chaperone‑mediated autophagy (CMA)-dependent degradation of TBK1. Stub1 directly interacts with TBK1 and catalyzes K27‑linked polyubiquitination at lysine 344 (K344) of TBK1, which enables recognition by the CMA chaperone HSC70 via a conserved KFDKQ CMA recognition motif. Subsequently, ubiquitinated TBK1 is delivered to lysosomes via HSC70 and the lysosomal membrane protein LAMP2A for degradation. This process is independent of macroautophagy and the ubiquitin - proteasome system. Myeloid‑specific Stub1 knockout mice show enhanced IFN‑I responses, lower viral loads, and improved survival rates upon viral infection. This study defines a Stub1-CMA signaling axis that fine‑tunes antiviral immunity and expands the regulatory scope of ubiquitin codes in selective protein degradation pathways.
    Keywords:  Chaperone‑mediated autophagy; HSC70; K27‑linked ubiquitination; LAMP2A; Stub1; TBK1
    DOI:  https://doi.org/10.1080/15548627.2026.2667376
  15. Sci Adv. 2026 May 15. 12(20): eadz3835
    mTOR-NAA10-C7orf50 axis senses nutritional status to coordinate ribosome biogenesis and autophagy.
    Jingyu Sun, Mei Yang, Qian Li, Jiawei Liang, Haiping Feng, Lijie Gao, Yun Wang, Hongmei Liu, Caixia Guo, Tie-Shan Tang.
      Cellular metabolism is precisely regulated in response to nutrient availability. As an extremely energy-consuming anabolic process, ribosome biogenesis should be tightly controlled in response to nutrient supply. However, how the nucleolus responds to different nutrient statuses remains poorly understood. Here, we show that C7orf50 is a nucleolus-localized protein and functions as a coordinator between ribosome biogenesis and autophagy, acting as what we term a "nutrient-responding nucleolar factor." C7orf50 undergoes reversible nucleolus-nucleoplasm translocation in response to nutrient deprivation and supply, with its nucleolus and nucleoplasm location dictating ribosome biogenesis and autophagic augmentation, respectively. The location-dependent function of C7orf50 is determined by acetylation at the lysine-71/lysine-72/lysine-76 residues by N-alpha-acetyltransferase 10, a substrate of mammalian target of rapamycin and a nutritional status-responsive acetyltransferase. In vivo and in vitro assays show that C7orf50 acts as an oncoprotein that promotes tumor growth. Our findings reveal a nucleolus-localized coordinating mechanism for the regulation of anabolism and catabolism transition by nutrient status.
    DOI:  https://doi.org/10.1126/sciadv.adz3835
  16. Nat Rev Nephrol. 2026 May 11.
    Selective autophagy in kidney health and disease.
    Ying Fu, Man J Livingston, Guie Dong, Anqun Chen, Juan Cai, Zheng Dong.
      The kidney is a highly metabolically active organ that relies on tightly regulated organelle turnover to maintain cellular homeostasis and support its energetic demands. Autophagy, once viewed primarily as a non-selective degradation mechanism, is now recognized to encompass specialized pathways - including mitophagy, lipophagy and endoplasmic reticulum-phagy - that mediate cargo-specific quality control of subcellular organelles. These selective programmes form an integrated network that couples stress- and nutrient-sensing regulators with core autophagy machinery and lysosomal capacity, generating cell-type- and context-dependent outputs across distinct nephron segments. Selective autophagy is a central determinant of renal stress adaptation, repair and disease progression. In acute kidney injury, in transition from acute kidney disease to chronic kidney disease and in diabetic kidney disease, selective autophagy preserves organelle homeostasis; however, insufficient, excessive or mistimed autophagic flux drives tubular injury, immune remodelling and fibrosis. Lysophagy, Golgiphagy and nucleophagy are emerging pathways of selective autophagy that might also contribute to the renal stress-response network. Therapeutic strategies that target selective autophagy in the kidney will require carefully timed and precise cell-specific modulation, as well as biomarker-guided patient stratification, to improve efficacy and avoid adverse effects.
    DOI:  https://doi.org/10.1038/s41581-026-01082-0
  17. Cardiol Rev. 2026 May 11.
    Understanding Dysfunctional Autophagy and Mitophagy in Inflammatory Cardiovascular Disease.
    Michael Kaiser, Toni-Ann Lewis, Michael Malekan, Manish A Parikh, Gioia Turitto, William H Frishman, Stephen J Peterson.
      Mitochondria are critical cellular powerhouses that produce adenosine triphosphate to maintain the structure and integrity of the cell. Mitochondria generate 90% of the energy of a cell. Chronic inflammation causes damage to mitochondria. When enough mitochondria are dysfunctional, the involved organ will suffer. Mitochondria become dysfunctional in the setting of chronic inflammation. Under noninflammatory conditions, the body generates new mitochondria (mitochondrial biogenesis) and removes old and damaged mitochondria via mitophagy. When mitochondria are damaged, they "spontaneously" leak out reactive oxygen species, mitochondrial DNA, and damage-associated molecular patterns, generating erroneous innate immune responses. Autophagy is a recycling and housekeeping process that removes dysfunctional components, organelles, and proteins, promoting the recovery and maintenance of cell health. Mitophagy is a specific variant of this process that removes dysfunctional mitochondria from the cell. Mitophagy declines with age, allowing dysfunctional mitochondria to accumulate, and chronic inflammation leads to cardiovascular disease (CVD). In CVD, impairment of both autophagy and mitophagy leads to more chronic inflammation, characterized by hyperactivation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a key component of the immune system. Once activated, it triggers inflammation, leading to excessive cytokine activity, proinflammatory macrophage polarization, pyroptosis, and increased immune cell infiltration into cardiac and vascular tissues. Pyroptosis is a form of inflammatory cell death triggered by programmed cues; however, in autoimmunity and cancer, when overactivated, this process can become detrimental. Adequate regulation of these events reduces oxidative stress, inflammatory cascades, fibrosis, and maladaptive remodeling, thereby improving overall cardiovascular health. Targeted therapeutic enhancement of autophagy and mitophagy represents a promising strategy to modulate immune-driven pathology and improve outcomes in cardiovascular conditions. We will review the mechanisms of how this inflammation causes CVD.
    Keywords:  NLRP3 inflammasome; atherosclerosis; autophagy; cardiovascular disease; cytokine release; endothelial dysfunction; heart failure; immune cell infiltration; inflammasome crosstalk; inflammation; innate immunity; ischemia-reperfusion injury; macrophage polarization; mitochondrial DAMPs; mitophagy; oxidative stress; pyroptosis; redox signaling; sterile inflammation; therapeutic modulation
    DOI:  https://doi.org/10.1097/CRD.0000000000001302
  18. Methods Mol Biol. 2026 ;3039 173-179
    Methods for Autophagy Detection by Fluorescence Microscopy.
    Xiaoye Ke, Xianglong Zhang, Xiangxiang Zhang.
      Fluorescence microscopy is pivotal for investigating autophagy's role in plant antiviral immunity. Here, we present a standardized procedure using complementary probes, CFP-ATG8f for autophagosomal structures and monodansylcadaverine (MDC) for autophagic vacuoles, to assess autophagy during viral infection. This combined CFP-ATG8f and MDC staining system provides a powerful, reproducible method for evaluating autophagic activity in plant-virus interactions.
    Keywords:  Autophagy; CFP-ATG8f; Confocal microscopy; MDC staining
    DOI:  https://doi.org/10.1007/978-1-0716-5300-5_20
  19. Nat Aging. 2026 May 14.
    Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.
    Jun-Ping Pan, Ping-Jie Wang, Jianying Zhang, Anne-Brita Knapskog, Leiv Otto Watne, He-Ling Wang, Maria Jose Lagartos-Donate, Sofie Lautrup, Li-Peng Mao, Qian Wang, Zhi-Peng Ling, Shi-Qi Zhang, Tomás Schmauck-Medina, Ruixue Ai, Trine Holt Edwin, Tianjiao Zhang, Ingvild Saltvedt, Rannveig Sakshaug Eldholm, Annabel Smith, Kateřina Veverová, Domenica Caponio, Asgeir Kobro-Flatmoen, Huanhuan Pang, Zijian Wang, Haoyun Wang, Li-Juan Gao, Nathalie Bodd Halaas, Garry Wong, Martin Vyhnalek, Oscar Junhong Luo, William A McEwan, Jon Storm-Mathisen, Li Gan, Zeping Hu, Henrik Zetterberg, Menno P Witter, Dag Aarsland, Geir Selbæk, Guobing Chen, Evandro Fei Fang.
      ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01108-z
  20. Autophagy Rep. 2026 ;5(1): 2665907
    A review of autophagy in the pancreas: normal physiology and pathophysiology.
    Miles Piper, Conan Kinsey.
      Autophagy is a complex cellular process of cellular degradation that is essential for healthy pancreatic function and, when perturbed, can result in pathological states such as pancreatitis, diabetes, and cancer. Extremes in both activation and inhibition can lead to inflammation, cell damage, and organ dysfunction. Pharmacologic targeting of autophagy to restore homeostasis may provide a therapeutic benefit to various pancreatic pathological processes. In this review, we discuss the current understanding of how autophagy maintains normal pancreatic function and is perturbed in various pancreatic disease states, including opportunities for potential therapeutic intervention.
    Keywords:  Autophagy; diabetes; pancreas; pancreatic cancer; pancreatitis
    DOI:  https://doi.org/10.1080/27694127.2026.2665907
  21. Autophagy. 2026 May 14. 1-20
    Formation and function of a novel Atg21-retromer complex in S. cerevisiae.
    Noreen Strubel, Jan Förster, Florian Kramer, Michael Thumm.
      Atg18, Atg21 and Hsv2 are homologous proteins that fulfill macroautophagic/autophagic and non-autophagic functions. We now found that Atg21 interacts with Pep8/Vps26, Vps29 and Vps35, the components of the cargo selective complex of the retromer. We identified Atg21 residues required for retromer binding and focused on two of them. The first, T106, is part of an STS-motif, which also mediates Atg18-binding to the retromer, while in Hsv2 this motif is not conserved. As a second retromer binding residue, we identified D28 of Atg21. Interestingly, the corresponding D45 of Hsv2 also confers retromer binding, but the analogous E34 of Atg18 does not. Together, Atg18 uses binding residue 1, while Atg21 uses 1 and 2 and Hsv2 only 2. During autophagy, Atg21 organizes the Atg8-lipidation machinery by interacting with Atg16 via the bottom side of its β-propeller. Partial overlap between the Atg16 binding residues and the retromer binding residues indicates mutually exclusive interaction. Indeed, lack of Atg16 enhances Atg21 binding to the retromer. The Atg21-retromer shows vacuole fission activity, which requires both retromer binding residues and the membrane-bending activity of its loop 6 C/D. Additionally, overexpression of Atg21 led to mislocalization of the Prc1/carboxypeptidase Y cargo receptor Pep1/Vps10 from the Golgi to Vps17-positive endosomes and to Prc1 secretion. We detected a cross-talk among the different retromer complexes. In the absence of the canonical retromer component Vps5, more Atg21-retromer complexes were formed. Furthermore, the vacuole hyper-fragmentation of vps17Δ cells cooperatively required Atg18 and Atg21. Along this line, we found that Atg21 interacts with Atg18 and Hsv2.Abbreviation: Atg: autophagy related, CSC: cargo specific complex (of the retromer), PAS: phagophore assembly site, Prc1/CPY/carboxypeptidase Y: proteinase C, PROPPIN: beta-propeller that binds phosphoinositides.
    Keywords:  Atg18; Atg21; Hsv2; PROPPIN; Vps35; retrograde transport; retromer; vacuolar fragmentation
    DOI:  https://doi.org/10.1080/15548627.2026.2671342
  22. Mitochondrion. 2026 May 12. pii: S1567-7249(26)00057-7. [Epub ahead of print]90 102167
    Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
    Ayumu Sugiura, Kohta Nakamura, Heidi M McBride, Yasushi Okazaki.
      Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.
    Keywords:  Lysosomes; Mitochondria; Mitochondrial-derived vesicles; Peroxisomes
    DOI:  https://doi.org/10.1016/j.mito.2026.102167
  23. Mol Neurobiol. 2026 May 15. pii: 630. [Epub ahead of print]63(1):
    Mechanisms of Action of FUNDC1 in Cerebral Ischemia-Reperfusion Injury.
    Xin-Yi Zou, Luo-Yang Cai, Jin Zhang, Ying Yuan, Jie Song, Zhao-Duan Hu, Rui Peng, Xiao-Feng Ruan, Xiao-Ming Zhang.
      Cerebral ischemia-reperfusion injury (CIRI) refers to a cascade of pathological events initiated by the restoration of blood flow to ischemic brain regions in patients with cerebral infarction. This process leads to mitochondrial dysfunction through mechanisms including oxidative stress, calcium overload, inflammation, and impaired energy metabolism. FUN14 domain containing 1 (FUNDC1), a key receptor protein involved in mitochondrial autophagy, plays a crucial protective role in CIRI by regulating mitophagy and maintaining mitochondrial quality control. This function is governed by the dynamic phosphorylation and dephosphorylation of FUNDC1, which finely modulate the activation and inhibition of mitophagy, thereby attenuating mitochondrial dysfunction. Moreover, FUNDC1 is implicated in mitochondrial fission, the clearance of unfolded proteins, mitochondrial iron metabolism, and inter-organelle communication, collectively contributing to the regulation of cellular metabolism and immune responses. Therefore, targeting FUNDC1-mediated mitophagy to restore mitochondrial quality control and reduce mitochondrial dysfunction represents a promising therapeutic strategy for CIRI. This review summarizes the role of FUNDC1 in mitochondrial dynamic homeostasis, inter-organelle communication, and CIRI, highlighting its potential as a therapeutic target.
    Keywords:  Cerebral ischemia-reperfusion injury; FUNDC1; Mitochondrial autophagy; Mitochondrial dysfunction; Receptor protein
    DOI:  https://doi.org/10.1007/s12035-026-05923-8
  24. Sci Rep. 2026 May 15.
    Small CD63 + CD81+ extracellular vesicles induce autophagy via the FOXO3a pathway in pancreatic cancer cells during starvation.
    Daniel Grasso, Maximiliano A Diaz, Laura Sobrado, Valentín Yzetta, Marcela A Cucher, Maria L Cerutti, Daniela L Papademetrio, Elida Alvarez, Maria Noé Garcia.
      Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive malignancy expected to become the second leading cause of cancer-related deaths by 2040. A hallmark of PDACs is the highly desmoplastic and hypovascularized nature of its microenvironment, which enables PDAC cells to adapt and survive under conditions of low oxygen and nutrient deprivation through various cellular mechanisms. Among these processes, autophagy has emerged as a key response mechanism to cope with these adverse conditions. Consequently, a deeper understanding of the molecular events driving autophagy could pave the way for the development of new and more effective treatments for PDAC. In this context, we provide evidence of novel pathway mediated by extracellular vesicles (EVs) that promotes autophagy in a paracrine manner in PDAC cells in response to starvation. Our findings indicate that, under starvation conditions, EVs-associated tetraspanins, namely CD9, CD63 and CD81, mobilize towards domains-like structures within the plasma membrane of PDAC cells. Correspondingly, a specific release of small EVs (sEVs) is observed in the starved cells. Notably, sEVs derived from starved cells, but not those from cells at basal conditions, strongly induce the autophagy pathway in PDAC cells cultured with optimal nutritional media. Interestingly, this ability to induce autophagy is specific to CD63/CD81 double-positive sEVs and is effective even in non-tumoral pancreatic cells. This sEVs-mediated autophagy is, at least partially, mediated by the activation of the FOXO3a pathway. It is worth noting that, although EVs release returns to basal level after 1 h of recovery following starvation, these EVs retain a capacity to induce autophagy, suggesting a decupling between quantity and quality of secreted vesicles. Our results demonstrate that pancreatic cancer cells in nutrient-deprived environments release specific sEVs that, in turn, activate the FOXO3a pathway and autophagy flux in recipient cells.
    Keywords:  Autophagy; Extracellular vesicles; Pancreatic cancer
    DOI:  https://doi.org/10.1038/s41598-026-52731-0
  25. Autophagy. 2026 May 12. 1-18
    Intracellular lipopolysaccharide binds RETREG1/FAM134B to regulate ER remodeling upon bacterial infection.
    Yi-Lin Cheng, João Mello-Vieira, Adriana Covarrubias-Pinto, Alexis Gonzalez, Santosh Kumar Kuncha, Chun Kew, Kaiyi Zhang, Muhammad Awais Afzal, Nour Diab, Sophia Borchert, Siou-Ying Hong, Timothy Chun Huang, Wenbo Chen, Uxía Gestal Mato, Mathias Walter Hornef, Christian A Hübner, Michael Hensel, Ivan Dikic.
      Selective autophagy of the endoplasmic reticulum (ER), termed ERphagy or reticulophagy, plays a key role in organelle remodeling and cellular homeostasis. However, whether and how ERphagy is regulated during Gram-negative bacteria infection to influence host responses remains unclear. Here, we show that Salmonella enterica serovar Typhimurium releases lipopolysaccharide (LPS) that colocalizes with RETREG1/FAM134B, a reticulon-like ER-resident receptor for ERphagy. Cytosolic delivery of LPS, either during infection or via transfection, markedly increases RETREG1- and LC3B-decorated ER fragments. Mechanistically, affinity-isolation assays demonstrate that LPS directly binds RETREG1 through interactions between lipid A and positively charged residues within its amphipathic helices and C-terminal region. This interaction promotes RETREG1 oligomerization and drives ER membrane fragmentation, a process further amplified by the O-antigen moiety of LPS. The resulting ER fragments accumulate around LC3-positive Salmonella-containing vacuoles, facilitating bacterial clearance. Importantly, both intracellular and extracellular Salmonella exploit outer membrane vesicles (OMVs) to deliver LPS into the host cytosol, triggering RETREG1 activation and ER remodeling. Collectively, our findings reveal a previously unrecognized host response by which LPS of Gram-negative bacteria are sensed by the host ERphagy machinery to promote xenophagy and enhance antibacterial defense.Abbreviations: AH: amphipathic helix; BMDMs: bone-marrow-derived macrophages; Co-IP: co-immunoprecipitation; BafA1: bafilomycin A1; Cterm: C-terminal region (Cterm); CFU: colony-forming units; DAPI: 4',6-diamidino-2-phenylindole; ER: endoplasmic reticulum; EPEC: enteropathogenic Escherichia coli; GBP: guanylate binding protein; Gm12250/IRGB10: predicted gene 12250; KDO: keto-3-deoxy-octonate; LPR: lipid-to-protein ratio; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mtLIR: LC3B-interacting region mutant; MDP: muramyl dipeptide; OMVs: outer membrane vesicles; O-Ag: O-antigen; OmpA: outer membrane protein A; RHD: reticulum homology domain; R-LPS: rough-LPS; S-LPS: smooth-LPS; SCVs: Salmonella-containing vacuoles; SFB: S-protein-FLAG-streptavidin binding peptide; TM: transmembrane domain; TEM: transmission electron microscopy; WT: wild-type.
    Keywords:  ER remodeling; RETREG1; Salmonella; lipopolysaccharide; outer membrane vesicles; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2669978
  26. Cells. 2026 Apr 29. pii: 813. [Epub ahead of print]15(9):
    Autophagy-Neuroinflammation Axis in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.
    Liyuan Sun, Yong Zou, Lifeng Wang.
      Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy-neuroinflammation axis in neurodegenerative disorders.
    Keywords:  autophagy; mechanisms; neurodegenerative diseases; neuroinflammation; therapeutic strategies
    DOI:  https://doi.org/10.3390/cells15090813
  27. Plants (Basel). 2026 Apr 28. pii: 1350. [Epub ahead of print]15(9):
    NBR1-Mediated Selective Autophagy in Plant Development and Stress Responses.
    Xinye Li, Yali Duan, Jiyang Zhou, Peifeng Yu.
      Autophagy is a conserved degradation pathway essential for cellular homeostasis in plants. Selective autophagy confers cargo specificity through receptors, among which NEIGHBOR OF BRCA1 GENE1 (NBR1) is one of the best-characterized. NBR1 mediates the selective turnover of ubiquitinated or stress-damaged cargoes, including protein aggregates and damaged organelles, by linking them to ATG8-decorated autophagosomes via its AIM and UBA domains. This process supports proteostasis, plant development, and adaptation to abiotic stresses, including heat, drought, chilling, salinity, and heavy metals, as well as biotic stresses from bacteria, fungi, viruses, and oomycetes. In this review, we summarize current advances in understanding NBR1 structure, evolutionary conservation, and cargo recognition mechanisms, and highlight its interplay with phytohormone signaling and the ubiquitin-proteasome system (UPS) in shaping plant growth and stress resilience.
    Keywords:  NBR1; protein degradation; selective autophagy; stress adaptations
    DOI:  https://doi.org/10.3390/plants15091350
  28. Aging Cell. 2026 May;25(5): e70539
    BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.
    Zhouyang Deng, Hailong Han, Caifang Wang, Wen Zhong, Zhengqing Wan, Dan Zhou, Ye Chen, Yanni Peng, Zongzhao Zhai, Kai Yuan, Ruoxi Wang, Zhuohua Zhang.
      Aging is a major risk factor for numerous diseases, including degenerative and metabolic disorders. Cumulative mitochondrial damage, elevated reactive oxygen species (ROS), and impaired mitophagy are hallmarks of aging. In this study, we generated a Drosophila version of the mito-SRAI reporter to monitor mitophagy in vivo and demonstrated an age-dependent decline in muscle mitophagy, accompanied by the accumulation of insoluble proteins, increased ROS levels, and mitochondrial damage. Overexpression of BNIP3 preserved muscle homeostasis by enhancing mitophagy, maintaining mitochondrial integrity, and suppressing ROS accumulation. Importantly, muscle-specific expression of BNIP3 in indirect flight muscles extended lifespan and alleviated age-associated neurodegenerative phenotypes, including protein aggregation, β-galactosidase accumulation, and pathological vacuolization in the brain. Mechanistically, BNIP3 inhibited ROS-mediated activation of Relish, thereby reducing expression of antimicrobial peptide (AMP) genes. These findings identify BNIP3 as a key regulator of aging that links mitochondrial quality control to systemic aging and neurodegeneration. Moreover, our results provide direct evidence of muscle-to-brain signaling, revealing a non-autonomous mechanism by which muscle mitophagy mitigates age-related neurodegeneration.
    Keywords:  BNIP3; aging; inflammation; mitophagy; neurodegeneration; non‐autonomous regulation
    DOI:  https://doi.org/10.1111/acel.70539
  29. Geroscience. 2026 May 13.
    Bench to bedside: is rapamycin headed for the docTOR?
    Dudley W Lamming.
      Almost a century ago, calorie restriction (CR) was identified as a robust intervention for extending lifespan and healthspan, a discovery that captured the imagination of both scientists and the public. If the powerful mechanisms engaged by CR can be uncovered and harnessed through a pill, humans might be able to live longer and healthier lives. Here, we will discuss the evolution of rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, from an immunosuppressant to the most reproducible pharmacological geroprotector in geroscience. This is a rapidly evolving field, with the number of basic science studies, clinical trials, and off-label use of mTOR inhibitors by the general public expanding quickly. We review findings in model organisms that have revealed potent benefits of rapamycin not only for longevity but for the function of multiple organ systems and on the hallmarks of aging. We review completed and ongoing clinical trials of rapamycin and analogs for diseases of aging in humans, and discuss the challenges and side-effects of rapamycin that may limit its translation from the laboratory to the clinic. While the jury is still out, we conclude that rapamycin-or molecules that similarly act to inhibit mTOR-may yet realize the century-old dream of extending healthspan and lifespan with a small molecule.
    Keywords:  Calorie restriction; Malnutrition; Rapamycin
    DOI:  https://doi.org/10.1007/s11357-026-02306-8
  30. Autophagy. 2026 May 14.
    PRKN-IMMT/MIC60 axis promotes myocardial ischemia-reperfusion injury via lysosomal degradation of GPX4.
    Xi Chen, Shuhan Liu, Mengqi Jiang, Mingyu Wei, Shuwan Xu, Jin-Yi Lin, Ze-Bo Huang, Pengxin Xie, Jixiang Cao, Hua Yang, Yun Bai, Guang Lu, Ming Cui.
      Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection. Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.
    Keywords:  Ferroptosis; IMMT/MIC60; PRKN; lysosome; mitochondria; myocardial ischemia reperfusion injury
    DOI:  https://doi.org/10.1080/15548627.2026.2674713
  31. Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261451671
    ER-driven Contact Sites in Autophagosome Biogenesis Sequence.
    Juliane Da Graça, Dobrawa Amiri Czajkowski, Etienne Morel.
      Autophagosome biogenesis is a highly coordinated membrane remodeling process that relies on the de novo formation and expansion of the phagophore, yet the cellular principles governing its spatial and temporal organization remain incompletely understood. Accumulating evidence now places the endoplasmic reticulum (ER) at the center of this process, not merely as a membrane source, but as a dynamic scaffold that organizes phagophore assembly through extensive membrane contact sites with multiple organelles. ER-mediated contacts with endosomes, mitochondria, the plasma membrane, and ER-Golgi intermediates create specialized microenvironments that integrate signaling, lipid transfer, vesicle formation and trafficking, and biophysical constraints to drive phagophore nucleation and growth. These contact sites enable the coordinated mobilization of diverse membrane carriers and autophagy regulators in a stress- and context-dependent manner. In this review, we discuss how ER-driven membrane contact sites orchestrate autophagosome biogenesis, highlight emerging mechanistic and biophysical concepts, and consider their broader implications for cellular stress adaptation and disease.
    Keywords:  ER-contact sites; autophagosome biogenesis; lipid transfer proteins
    DOI:  https://doi.org/10.1177/25152564261451671
  32. Analyst. 2026 May 11.
    Selective detection of lipophagy with a highly specific lipid droplet probe.
    Shixiong Wen, Xiaoxue Zou, Jianing Liu, Jiahuai Han, Shoufa Han.
      Lipophagy, the autophagic degradation of lipid droplets (LDs) by lysosomes, is an important route for maintaining LD homeostasis. Tools for lipophagy detection facilitate research in LD biology. Herein, we report LD-Blue, a highly specific LD probe, for tracking dynamic formation of LDs and detection of lipophagy. Upon lipophagy, LD-Blue chaperoning host LDs is delivered into lysosomes. By using the co-localization co-efficiency of LD-Blue and LysoTracker Red as the readout of lipophagy, we observed lipophagy induced by serum deprivation but not acute nutrient starvation as well as lipophagy inhibition by chloroquine and Bafilomycin A1. With the established fidelity of the LD-Blue-based co-localization assay for lipophagy, monensin is identified to be a potent inducer of lipophagy.
    DOI:  https://doi.org/10.1039/d5an01241d
  33. Cell Struct Funct. 2026 May 09.
    Loss of macroautophagy results in abnormality of the endoplasmic reticulum in insulin-secreting MIN6 cells.
    Asako Kishimoto, Shunsuke Saito, Byungseok Jin, Shigeomi Shimizu, Satoko Arakawa, Kazutoshi Mori.
      Macroautophagy is a highly conserved system that degrades various materials inside the cell ranging from proteins to organelles. Atg5 is a protein essential for the formation of autophagosomes, which sequester materials by double membrane and degrade them after fusion with lysosomes. MIN6 cells derived from mouse pancreatic β cells retain the ability to secrete insulin in response to a change in glucose concentration from low to high. We knocked out the Atg5 gene in MIN6 cells and identified an abnormality in the endoplasmic reticulum (ER) under normal culture conditions using electron microscopy. The ER was slightly enlarged and the ER membrane was ruptured at some places adjacent to inclusion body-like structures. Numerous granule-like structures were accumulated in the lumen of the ER, some of which appeared to have leaked into the cytoplasm. These abnormalities caused ER stress, resulting in activation of all three pathways (IRE1, PERK, and ATF6) of the unfolded protein response but no induction of apoptosis. We also observed the activation of alternative autophagy/Golgi membrane-associated degradation in Atg5-KO MIN6 cells, but this was insufficient for the removal of a majority of these granule-like structures from the ER. Thus, macroautophagy but not activation of the unfolded protein response or Golgi membrane-associated degradation is essential for the homeostasis of the ER in MIN6 cells.Key words: autophagy, endoplasmic reticulum, unfolded protein response, proinsulin, Golgi membrane-associated degradation.
    Keywords:  Golgi membrane-associated degradation; autophagy; endoplasmic reticulum; proinsulin; unfolded protein response
    DOI:  https://doi.org/10.1247/csf.26016
  34. Medicine (Baltimore). 2026 May 08. 105(19): e47600
    Mitophagy in ophthalmic pathologies: Molecular mechanisms and therapeutic implications.
    Yibo Han, Jiaojiao Feng, Xiaoqi Gong, Guodong Tang, Yixue Yin, Jing Li, Yuxi Liu, Jun Zhang, Jike Song, Hongsheng Bi.
      Mitophagy, a selective autophagic process responsible for the degradation of dysfunctional mitochondria, serves as a critical regulator of cellular homeostasis. Despite its emerging significance in ocular pathophysiology, comprehensive analyses bridging molecular mechanisms to clinical translation remain scarce. The retina, with its high metabolic demands and reliance on mitochondrial bioenergetics, is particularly vulnerable to mitophagic dysregulation, which has been mechanistically linked to the pathogenesis of major ophthalmic disorders. This review systematically elucidates the molecular architecture of mitophagy, focusing on its dual roles in disease progression and cytoprotection across glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). By integrating mechanistic insights with therapeutic implications, we not only delineate conserved regulatory pathways (e.g., PINK1 [PTEN-induced kinase 1]/Parkin, BNIP3 [BCL2/adenovirus E1B 19 kDa interacting protein 3], FUNDC1 [FUN14 domain containing 1]) but also propose a roadmap for targeting mitophagic checkpoints through precision pharmacology and combinatorial regimens. Our synthesis underscores the urgency of translating mitophagy modulation into clinical strategies to address unmet needs in retinal degenerative diseases.
    Keywords:  age-related macular degeneration (AMD); diabetic retinopathy (DR); glaucoma; mitophagy; oxidative stress; regulation of autophagy
    DOI:  https://doi.org/10.1097/MD.0000000000047600
  35. Anal Chem. 2026 May 13.
    Fluorescence-On Imaging of Golgiphagy with a Golgi Apparatus-Specific Metabolic Lipid Labeling Probe Fluorogenic to Lysosomal Acidity.
    Jipeng Yao, Shixiong Wen, Jiahuai Han, Shoufa Han.
      The Golgi apparatus (GA) plays crucial roles in myriad biological processes, and aberrant Golgiphagy has been implicated in a number of pathological settings. Given the lack of suitable imaging tools for Golgiphagy and the propensity of chemical probes to dissipate from stressed organelles, we herein report Golgi-proRed, a pH probe covalently anchored on the GA inner membrane, for imaging of Golgiphagy by red fluorescence triggered upon autophagic delivery of GA into acidic lysosomes. The probe contains a GA-homing entity of blue-to-green fluorescence, a rhodamine-lactam entity that becomes red-emissive in acidic lysosomes, and a moiety of dibenzocyclooctyne (DBCO) for bioorthogonal conjugation with azido-phospholipids metabolically incorporated into the membrane of GA. Upon Golgiphagy, the membrane-anchored probe is codelivered with GA fragments into lysosomes, yielding red fluorescence that serves as the readout of Golgiphagy. The imaging fidelity for Golgiphagy is confirmed by starvation-induced red fluorescence, lysosome-dependent red fluorescence, and lack of such a signal in ATG5-knockout cells deficient in autophagy. With this method, we observed that obvious Golgiphagy occurred in iBMDM cells treated with nigericin and lipopolysaccharides (LPSs) or infected by Listeria monocytogenes. These results show the use of Golgi-proRed for sensitive detection of Golgiphagy in biological events and to screen Golgiphagy-inducing agents.
    DOI:  https://doi.org/10.1021/acs.analchem.5c07299
  36. Autophagy. 2026 May 14.
    The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62.
    Eui Jung Jung, Hye Yeon Kim, Tae Hyun Bae, Eun Nam Choi, Hyomin Lim, Minji Kim, Su Ran Mun, Yoon Jee Lee, Soojung Hahn, Dong Ryul Lee, Woo-Jae Park, Young Ho Suh, Yong Tae Kwon, Yeon Sung Son, Hee-Yeon Kim, Joo-Won Park.
      Central to the pathogenesis of type 2 diabetes (T2D) is the failure in insulin secretion from pancreatic β-cells associated with insulin resistance. The nuclear receptor RXRA/RXRα (retinoid X receptor alpha) is a transcriptional regulator of insulin secretion and systemic glucose metabolism. Here, we show that the macroautophagic/autophagic receptor SQSTM1/p62 (sequestosome 1) sequesters RXRA for lysosomal degradation to modulate glucose metabolism and insulin secretion. Under glucolipotoxicity, RXRA is released from SQSTM1 to inhibit mitochondrial respiration and insulin secretion and to induce lipogenesis. SQSTM1-dependent degradation of RXRA was reconstituted in vitro and mice using ATB1002, a chemical N-degron designed to bind and activate SQSTM1 as an N-recognin of the N-degron pathway. In prediabetic and T2D models, SQSTM1 agonists induced the lysosomal degradation of RXRA, and enhanced glucose-stimulated insulin secretion and insulin responsiveness. These results identify SQSTM1 as a master regulator in glucose metabolism and insulin secretion, providing a therapeutic means to treat T2D.
    Keywords:  Autophagy-lysosome system; N-degron pathway; glucose homeostasis; insulin resistance; insulin secretion; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1080/15548627.2026.2674715
  37. bioRxiv. 2026 Feb 24. pii: 2026.02.22.707197. [Epub ahead of print]
    Zinc excess promotes lysosome remodeling by activating HLH-30/TFEB through the action of the high zinc sensor HIZR-1.
    Ciro Cubillas, Hanwenheng Liu, Krupa Deshmukh, Adelita Mendoza, Daniel L Schneider, Daniel Herrera, Chen Zhao, John T Murphy, John Edwards, Abhinav Diwan, Kerry Kornfeld.
      Zinc is an essential element that plays many roles in animals. Since excess zinc is toxic, animals have evolved sophisticated mechanisms to achieve homeostasis. A conserved mechanism is to store excess zinc in specialized lysosomes, which contributes to zinc detoxification and provides a supply when zinc becomes limiting. In C. elegans excess zinc conditions promote an increase in lysosome-related organelles called bilobed granules. Defining how zinc-regulated transcription drives the observed lysosome remodeling is key to understanding zinc homeostasis processes. Here we describe a positively regulated zinc cascade controlled by hizr-1 and hlh-30/TFEB , which encode the C. elegans high zinc sensor and the master regulator of the autophagy-lysosomal pathway, respectively; essential for connecting excess zinc homeostasis to lysosome biogenesis and remodeling. Our transcriptomic, genetic, and bioinformatic studies indicate that hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome genes under excess zinc conditions. In our regulatory model, zinc binding activates HIZR-1 protein, which accumulates in the nucleus and activates genes containing the HZA enhancer, including hlh-30 . HLH-30 protein accumulates in the nucleus and activates genes containing the E-box enhancer. Genetic analysis of loss-of-function mutants demonstrated that both hizr-1 and hlh-30 are necessary for animals to tolerate excess zinc. Furthermore, HLH-30 promotes the increase in the number of acidified compartments, whereas HIZR-1 promotes the increase in the volume of the expansion compartment. These results define a genetic pathway that responds to excess zinc by increasing the number of lysosome-related organelles and their capacity to store and detoxify cytosolic zinc.
    DOI:  https://doi.org/10.64898/2026.02.22.707197
  38. Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]
    AMPK: a master regulator of mitochondrial quality and quantity.
    Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.
    Keywords:  endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.008
  39. Ageing Res Rev. 2026 May 07. pii: S1568-1637(26)00149-2. [Epub ahead of print]119 103157
    Urolithin A: Potential to enhance autophagic clearance and mitigate neuroinflammation in Alzheimer's disease.
    Jiawei Xiang, Junjing Xu, Yong Zhang, Xuehong Liu.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia in older adults. The presence of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) constitutes the two principal neuropathological features of AD. However, current therapies targeting only Aβ or tau remain suboptimal, likely due to intrinsic neuronal and glial dysfunction in affected brain regions. Urolithin A (UroA) is a widely recognized mitophagy activator with potent antioxidant and anti-inflammatory properties. Current clinical studies confirm UroA's safety in humans and its broad benefits for mitochondrial health. Preclinical data show enhanced lysosomal and mitochondrial quality in neurons and glia during AD progression. Given current AD pathology insights, UroA shows significant therapeutic promise. The AMPK/SIRT/mTOR signaling axis regulates cellular adaptation to metabolic stress and energy balance, and is significantly dysregulated in AD progression. This review comprehensively evaluates the structural and biological characteristics of UroA, with a focus on its role in enhancing mitophagy, promoting lysophagy, and mitigating neuroinflammation in the context of AD. However, current research has not clarified how UroA enhances mitochondrial and lysosomal function while suppressing neuroinflammation. This report further investigates the potential interplay between UroA and the AMPK/SIRT/mTOR signaling pathway, elucidating a plausible mechanism through which UroA regulates the autophagic-lysosomal system and mitigates neuroinflammation via modulation of this axis.
    Keywords:  Alzheimer's disease; Lysophagy; Mitophagy; Neuroinflammation; Urolithin A
    DOI:  https://doi.org/10.1016/j.arr.2026.103157
  40. Autophagy. 2026 May 14. 1-20
    The multifaceted regulation of autophagy protein ATG16L1 and its implications in human diseases.
    Fujing Wei, Zhenzhen Liu, Xiaoying Yu, Yinqi Sun, Yuanyuan Zhao, Yu Wang, Ziling Feng, Xiaozhu Zhao, Xiaoxue Ke, Aimin Yang, Hongjuan Cui.
      ATG16L1 (autophagy related 16 like 1) is a core macroautophagy/autophagy protein essential for autophagosome formation. It also functions in non-canonical autophagy pathways such as LC3-associated phagocytosis (LAP) and in other processes including immunity, inflammation, and membrane trafficking. This review synthesizes recent advances and proposes that ATG16L1 functions as a central molecular integrator governed by a multi-layered regulatory code. This framework includes genetic polymorphisms, transcriptional control, and diverse post-transcriptional and post-translational mechanisms. We detail how these regulatory layers collectively fine-tune ATG16L1 function in response to cellular stress. Dysregulation of this network contributes broadly to human diseases including inflammatory bowel disease, cancer, and neurodegenerative disorders. Notably, the functional impact of specific regulatory events is highly context dependent, a principle exemplified by the Crohn disease-associated T300A polymorphism. Deciphering this regulatory landscape and its crosstalk with both autophagy-dependent and autophagy-independent functions positions ATG16L1 as a pivotal node in cellular homeostasis and as an emerging therapeutic target.Abbreviations ATG: autophagy related; CASM: conjugation of Atg8-family proteins to single membranes; CCD: coiled-coil domain; CEBPA/CEBPα: CCAAT enhancer binding protein alpha; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; circRNA: circular RNA; CPT1A: carnitine palmitoyltransferase 1A; CREB: cAMP responsive element binding protein; CSNK2: casein kinase 2; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GJA8/connexin 50: gap junction protein alpha 8; H/R: hypoxia-reoxygenation; HDAC: histone deacetylase; KAT2B/PCAF: lysine acetyltransferase 2B; KDM1A: lysine demethylase 1A; LAP: LC3-associated phagocytosis; lncRNA: long non-coding RNA; LRRK2: leucine rich repeat kinase 2; m6A: N6-methyladenosine; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; miRNA/MIR: microRNA; Mtb: Mycobacterium tuberculosis; ncRNA: non-coding RNA; PE: phosphatidylethanolamine; PI3K: phosphoinositide 3-kinase; PRKA/PKA: protein kinase cAMP-activated; PPP1: protein phosphatase 1; RAB33B: RAB33B, member RAS oncogene family; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SETD7: SET domain containing 7, histone lysine methyltransferase; SQSTM1/p62: sequestosome 1; TNF/TNF-α: tumor necrosis factor; ULK: unc-51 like autophagy activating kinase; V-ATPase: vacuolar-type H+-translocating ATPase; VDR: vitamin D receptor; WIPI2B: WD repeat domain, phosphoinositide interacting 2B; YTHDF2: YTH N6-methyladenosine RNA binding protein F2; ZDHHC7: zDHHC palmitoyltransferase 7.
    Keywords:  ATG16L1; T300A polymorphism; autophagy; non-canonical autophagy; post-translational modifications; transcriptional regulation
    DOI:  https://doi.org/10.1080/15548627.2026.2672698
  41. Cell Prolif. 2026 May 14. e70226
    Tunnelling Nanotube-Mediated Lysosome Sharing Promotes Osteocyte Survival via Transcellular Autophagy.
    Jinbiao Qiang, Ronghao Jin, Tong Sha, Fang Zheng, Yijun Zhou, Yue Hu, Shuyu Zhang, Zhenming Yang, Mengdong Nie, Huanyu Luo, Xiaoduo Tang, Hao Guo, Zunxuan Xie, Jinwei Li, Hongchen Sun, Cangwei Liu, Ce Shi.
      Osteocytes, the central regulators of bone remodelling, are essential for maintaining bone homeostasis. Embedded in a nutrient-limited matrix and burdened by cumulative stress over their exceptionally long lifespan, how osteocytes sustain long-term viability remains elusive. Tunnelling nanotubes (TNTs) are newly described intercellular bridges that enable long-range transfer of organelles and have been implicated in stress adaptation. Here, we provide the first definitive identification of TNTs between cultured osteocytes, which exhibit canonical TNT morphology together with osteocyte-specific features. Functionally, osteocytic TNTs mediate intercellular transfer of membrane-bound cargo, predominantly lysosomes. Under nutrient deprivation, TNT formation and lysosome transfer are both increased, replenishing the lysosomal pool in stressed osteocytes. Transferred lysosomes then fuse with accumulated autophagosomes, thereby restoring impaired autophagic flux and suppressing apoptosis. This cytoprotective effect requires TNT integrity and intact autophagic flux. Although mitochondrial transfer is detectable, it does not confer comparable protection. The findings identify a transcellular autophagy pathway mediated by TNT-dependent lysosome sharing, revealing a previously unrecognized cooperative survival strategy among osteocytes. This work establishes a novel conceptual framework in osteocyte biology and suggests potential therapeutic avenues for bone diseases associated with osteocyte apoptosis and impaired bone remodelling.
    Keywords:  apoptosis; intercellular communication; lysosomes; mitochondria; osteocytes; transcellular autophagy; tunnelling nanotubes
    DOI:  https://doi.org/10.1111/cpr.70226
  42. Mech Ageing Dev. 2026 May 08. pii: S0047-6374(26)00043-6. [Epub ahead of print]231 112191
    Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
    YiFan Yan, Yuetong Li, Heng Ma.
      Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.
    Keywords:  Aging; Lysosome; Membrane contact sites; Mitochondria-lysosome contacts; Mitochondrial quality control; Organelle homeostasis
    DOI:  https://doi.org/10.1016/j.mad.2026.112191
  43. Mol Ther Adv. 2026 Mar 12. 34(1): 201687
    Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
    Burcak Ozes, Lingying Tong, Kyle Moss, Morgan Myers, Lilye Morrison, Edward Son, Tatyana A Vetter, Zarife Sahenk.
      Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
    Keywords:  AAV; BAG1; BAG3; MFM3; autophagy; myofibrillar myopathy; myotilinopathy; protein accumulation; protein aggregate myopathy
    DOI:  https://doi.org/10.1016/j.omta.2026.201687
  44. FASEB J. 2026 May 31. 40(10): e71812
    Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
    Ranran Zhao, Jican Zhao, Weiyi Xia, Wanjuan Yu, Huihui Zhou, Xuan Wang, Kansen Mai, Gen He, Chengdong Liu.
      The Integrated Stress Response (ISR) is a vital cellular mechanism that regulates cell survival during various stress conditions, including hypoxia. Activating transcription factor 4 (ATF4) is recognized as a key regulator of ISR, however, its role in hypoxic stress responses remain underexplored. In the present study, we generated an Atf4a-deficient zebrafish model to investigate the role of Atf4a in hypoxia tolerance, mitochondrial homeostasis, and cellular stress adaptation. The results showed that atf4a knockout led to significant growth impairment, endoplasmic reticulum and mitochondrial dysfunction, and disrupted energy metabolism, particularly under hypoxic conditions. We observed an increase in mitochondrial DNA and impaired mitochondrial morphology in Atf4a-deficient zebrafish. Metabolomic analysis revealed significant alterations in the pentose phosphate pathway and TCA cycle following atf4a knockout. Additionally, we observed increased mitochondrial oxidative stress and reduced antioxidant capacity in atf4a mutants. Atf4a-deficiency also led to decreased expression of the mitophagy-related gene p62 and parkin. Atf4a transcriptionally regulates the expression of parkin, suggesting that Atf4a regulates mitochondrial homeostasis through parkin-mediated mitophagy in zebrafish. These results underscore the critical role of Atf4a in maintaining cellular homeostasis, mitochondrial integrity, and metabolic adaptation during hypoxic stress, highlighting its potential as a therapeutic target for stress-related diseases.
    Keywords:  ATF4; ISR; hypoxia; mitophagy; parkin
    DOI:  https://doi.org/10.1096/fj.202502855R
  45. Cell Mol Biol Lett. 2026 May 13.
    Implications of ferritinophagy in cardiovascular diseases and its pharmacological modulation: underlying mechanisms and clinical translation strategies.
    Yan-Lin Wu, Ling Xiao, He-Ning Li, Lin-Xi Chen.
      Ferritinophagy is a crucial intracellular process mediated by the selective autophagy receptor nuclear receptor coactivator 4 (NCOA4), which plays a central role in maintaining iron homeostasis by regulating ferritin degradation. In recent years, its function as a key interface between autophagy and iron metabolism has attracted considerable attention owing to its pathophysiological relevance in cardiovascular diseases (CVDs). This review systematically delineates the molecular mechanisms of ferritinophagy, including the formation of the NCOA4-ferritin complex, lysosomal degradation pathways, and the multilayered regulatory networks involved. Particular focus is given to the dual role of ferritinophagy in cardiovascular pathology, encompassing myocardial ischemia-reperfusion injury (MIRI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM). While moderate ferritinophagy activity is essential for maintaining adequate cardiac iron supply, its excessive activation leads to labile iron accumulation, oxidative stress via the Fenton reaction, and ferroptosis, thereby exacerbating myocardial injury and pathological remodeling. Consequently, this article provides a comprehensive overview of pharmacological strategies targeting ferritinophagy, including direct inhibition approaches (e.g., NCOA4 small interfering RNA (siRNA) and lysosomal inhibitors) and indirect modulation strategies (e.g., ferroptosis inhibitors and natural compounds). Finally, challenges to clinical translation are addressed, particularly regarding tissue specificity, drug delivery efficiency, and long-term safety. Future research directions are proposed, including the development of organ-specific targeting strategies and the exploration of combination therapies, with the aim of offering novel insights and potential therapeutic avenues for the prevention and treatment of CVDs.
    Keywords:  Cardiovascular diseases; Ferritinophagy; NCOA4
    DOI:  https://doi.org/10.1186/s11658-026-00941-9
  46. Cell Death Dis. 2026 May 11.
    Proteasome inhibition enhances lysosome-mediated targeted protein degradation.
    Ahmed M Elshazly, Nayyerehalsadat Hosseini, Janakiram Vangala, Shanwei Shen, Victoria Neely, Xiaoyan Hu, Piyusha P Pagare, Hisashi Harada, Steven Grant, Senthil K Radhakrishnan.
      Proteasome inhibitor drugs are currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. These inhibitors cause accumulation of undegraded proteins, thus inducing proteotoxic stress and consequent cell death. However, cancer cells counteract this effect by activating an adaptive response through the transcription factor nuclear factor erythroid 2-related factor 1 (NRF1, also known as NFE2L1). NRF1 induces transcriptional upregulation of proteasome and autophagy/lysosomal genes, thereby reducing proteotoxic stress and diminishing the effectiveness of proteasome inhibition. While suppressing this protective autophagy response is one potential strategy, here we investigated whether this heightened autophagy could instead be leveraged therapeutically. To this end, we designed an autophagy-targeting chimera (AUTAC) compound to selectively degrade the anti-apoptotic protein Mcl1 via the lysosome. Our results show that this lysosome-mediated targeted degradation is significantly amplified in the presence of proteasome inhibition, in a NRF1-dependent manner. Mechanistically, AUTAC-driven Mcl1 clearance requires K63-linked ubiquitination by UBC13 and TRAF6 and recognition by the cargo receptor p62/SQSTM1. The combination of the proteasome inhibitor carfilzomib and Mcl1 AUTAC synergistically promoted cell death in both in vitro models, including wild-type and proteasome inhibitor-resistant multiple myeloma and lung cancer cells, and in mouse tumor xenografts. Thus, our work offers a novel strategy for enhancing proteasome inhibitor efficacy by exploiting the adaptive autophagy response. More broadly, our study establishes a framework for amplifying lysosome-mediated targeted protein degradation, with potential applications in cancer therapeutics and beyond.
    DOI:  https://doi.org/10.1038/s41419-026-08835-6
  47. Nat Chem Biol. 2026 May 14.
    A TerminaTOR of mTORC1 signaling.
    Diane C Fingar.
      
    DOI:  https://doi.org/10.1038/s41589-026-02200-6
  48. Mol Neurodegener Adv. 2026 ;2(1): 18
    The modifier matrix: emerging roles of ubiquitin-like proteins in Alzheimer's disease.
    Tingxiang Yan, Justine Vaquer, Wolfdieter Springer, Fabienne C Fiesel.
      Ubiquitin and ubiquitin-like proteins (UBLs) have emerged as critical regulators of protein homeostasis and cellular signaling, processes that are increasingly recognized as central to the pathogenesis of Alzheimer's disease (AD). This review explores the expanding roles of UBL modifiers, including SUMO, NEDD8, ISG15, UFM1, and ATG8/ATG12, in the development and progression of AD. We discuss how these post-translational modifications influence key pathological features of AD such as amyloid-beta accumulation and neurofibrillary tangles formation, as well as their impact on neuronal function, proteostasis, and neuroinflammation. Recent advances in our understanding of the enzymatic machinery mediating these modifications, and the interplay between different UBL proteins, offer new insights into the molecular mechanisms underlying AD. Furthermore, we highlight emerging therapeutic strategies targeting UBL pathways, which may provide novel avenues for intervention in AD. By integrating current findings, this review underscores the significance of UBL proteins in AD and identifies future directions for research aimed at unraveling their complex roles in neurodegeneration.
    Graphical abstract:
    Keywords:  ATG12; ATG8; Alzheimer’s disease; Amyloid-beta; ISG15; MAPT; NEDD8; SUMO; Tau; UFM1; Ubiquitin; Ubiquitin-like proteins
    DOI:  https://doi.org/10.1186/s44477-026-00031-2
  49. Biophys Rep. 2026 Apr 30. 12(2): 116-125
    The dual function of mitophagy in ferroptosis.
    Xiaoxuan Zeng, Xushan Ma, Yueping Bai, Jiaqi Li, Fan Yu.
      Ferroptosis is a new form of cell death driven by iron-dependent lipid peroxidation. Thus, it is closely related to the lipid and iron metabolism. Accumulating evidence has suggested mitochondria, the center of cell metabolism, are important regulators of ferroptosis. This is not surprising as mitochondria are also the center for lipid metabolism and iron metabolism, as well as redox balance. As the essential way of mitochondrial quality control, mitophagy may alleviate ferroptosis. On the other hand, the digestion of iron-rich mitochondria may provide ample sources for the activation of ferroptosis. This review describes these new findings about the interplay of mitophagy and ferroptosis and demonstrates the dual role of mitophagy in ferroptosis.
    Keywords:  Ferroptosis; Iron; Mitophagy; ROS
    DOI:  https://doi.org/10.52601/bpr.2025.240071
  50. Brain. 2026 May 12. pii: awag170. [Epub ahead of print]
    TIM-3-dependent lysosome biogenesis is required for myelin debris clearance in macrophages.
    Xiaodi Zhang, Ziqing Xu, Yingxue Zhang, Zheng Tong, Xiaolei Ren, Ying Xiao, Hao Chen, Na Han, Chunyang Li, Xuetian Yue, Zhuanchang Wu, Xiaohong Liang, Chunhong Ma, Pin Wang, Lifen Gao.
      Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the immune-mediated demyelination and neurodegeneration of the central nervous system. Phagocyte mediated myelin debris clearance is required for remyelination. TIM-3 is highly expressed on mononuclear macrophages and promotes the phagocytosis of apoptotic cells. Here, we report that TIM-3 enhances the clearance of myelin debris in experimental autoimmune encephalomyelitis (EAE), a model of MS. Tim-3 knockout (KO) exacerbated EAE severity, neuroinflammation, and demyelination by regulating mononuclear macrophages. TIM-3 promoted the phagocytosis and degradation of myelin debris by macrophages. Mechanistically, Tim-3 deficiency impaired lysosomal biogenesis and function, leading to lysosomal membrane permeabilization and disrupted lysosomal acidification, which further exacerbated neuroinflammation and demyelination. Notably, TIM-3 blocked the interaction of mTOR-TFEB to inhibit TFEB phosphorylation and facilitate its nuclear translocation, followed by increased expression of lysosomal genes critical for myelin degradation. Importantly, the IgV domain is necessary in TIM-3-mediated lysosomal regulation and myelin degradation. These findings highlight TIM-3 as a key regulator of lysosomal homeostasis and the clearance of myelin debris, suggesting that the IgV domain has promise as a therapeutic agent for treating demyelinating diseases such as MS.
    Keywords:  TFEB; TIM-3; lysosomal biogenesis; macrophage; multiple sclerosis; myelin debris clearance
    DOI:  https://doi.org/10.1093/brain/awag170
  51. Nat Aging. 2026 May 12.
    Hypoxia-induced autophagic degradation of HIF-1α attenuates cellular aging and extends mammalian lifespan.
    Chen Yang, Zeng Xu, Sha-Tong He, Gen-Jiang Zheng, Jian-Xi Wang, Fa-Zhi Zang, Jin-Quan Hu, Yun-Hao Wang, Wen-Yu Zhang, Chen-Fei Gao, Teng-Hui Zhang, Yang Ye, Hao Chen, Fan-Qi Kong, Xiao Lv, Lei Liang, Yue-Li Sun, Zhen-Wei Wang, Zi-Xi Wang, Peng Cao, Xiao-Dong Wu, Bo Gao, Ye Tian, Bo Hu, Hua-Jiang Chen.
      Organs age at different rates, yet the protective mechanisms contributing to decelerated aging in certain tissues remain unclear. Applying cross-tissue comparisons to molecular readouts of aging, here we report that the intervertebral disc (IVD) ages slowly. We link the rate of aging to the persistently hypoxic environment of the IVD, and its unique ability to degrade hypoxia-inducible factor-1α (HIF-1α) in nucleus pulposus cells through optineurin-mediated selective autophagy, thereby uncoupling hypoxia from HIF-1α accumulation and limiting cellular stress. Further, we developed a small-molecule HIF-1α-targeting autophagy-tethering compound (HATC) to pharmacologically export the protective mechanism to other tissues. In aged mice, systemic weekly administration of HATC reduced HIF-1α levels across multiple organs, ameliorated a range of age-related pathologies and significantly extended both median (~14%) and maximum lifespan (~12%). These findings define a regulatory axis in which HIF-1α degradation under hypoxia contributes to longevity, and support HATC as a geroprotective strategy to improve healthspan.
    DOI:  https://doi.org/10.1038/s43587-026-01124-z
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