bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–08–02
forty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
  2. A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.
  3. Vimentin intermediate filaments support autophagosome biogenesis at ER-endosome contact sites in response to starvation.
  4. Progerin Hinders Autophagy Flux at Its Final Stages in Hutchinson-Gilford Progeria Syndrome Cells, Preventing Its Own Autophagic Degradation.
  5. Endogenous autophagosome reporters reveal redundant and non-redundant roles of LGG-1 and LGG-2 in C. elegans neuronal autophagy.
  6. Spatiotemporal control of Atg2 association with the ER during autophagosome formation.
  7. Signatures of aging and disease in a single organelle.
  8. Host autophagy in Staphylococcus aureus infection: Mechanisms of clearance, evasion, and therapeutic intervention.
  9. KIF1A-mediated trafficking is required for neuronal autophagy in human neurons.
  10. Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
  11. Transport of endo-β-mannosidase AtEBM from the cytoplasm to the vacuole through the autophagy pathway in Arabidopsis.
  12. Inactivation of V-ATPase induces autophagy and ectopic Notch activation to promote intestinal stem cell differentiation in adult drosophila midgut.
  13. Trr1 (thioredoxin reductase 1) modulates ERphagy in aging via liquid-liquid phase separation.
  14. Nutrient stress activates RAB5B-mediated autophagy to remodel the synaptic proteome.
  15. Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
  16. The role of autophagy in protozoan infections.
  17. Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
  18. The tumor suppressor Tip60 inhibits TORC1 signaling in response to microbial acetate to promote autophagy and enterocyte differentiation.
  19. Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction.
  20. Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.
  21. Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
  22. Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
  23. Autophagy dysfunction in pancreatic acinar cells in acute pancreatitis: from molecular mechinery and trypsinogen activation to heterogeneity and therapeutic implications.
  24. GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTS ALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE.
  25. Nanomedicine-Mediated Autophagy Modulation in Placental Impairment Versus Cancers: A Narrative Review.
  26. Autophagy in MASLD: A Metabolic and Precision Medicine Perspective.
  27. A Golgi-bypass secretion mechanism for proTGFα involving TMED9 and GRASP65.
  28. PARP1 hyperactivity stalls translation and triggers stress granule formation following DNA damage.
  29. The glycolytic enzyme PGAM1 functions as a metabolic-autophagy checkpoint to coordinate growth and stress tolerance.
  30. Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
  31. Vacuolar protein sorting 4B is a novel regulator of osteoblast and adipocyte differentiation by activating autophagy signaling.
  32. Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
  33. Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
  34. Toxoplasma TgATG2 works with TgATG9 and TgProp1 to drive autophagic flux for parasite extracellular survival and persistence.
  35. Human GBP4 promotes TRIM21-BIP-dependent autophagy to restrict M. tuberculosis infection by preventing SORT1-mediated progranulin degradation.
  36. Interplay between RNA m6A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.
  37. TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
  38. Autophagy Modulation in Cancer Therapy: Navigating the Dual Roles to Overcome Chemoresistance.
  39. Autophagy prevents ER stress-induced Tight Junction barrier disruption via claudin-2 homeostasis.
  40. The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
  41. The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.
  42. Leveraging Supramolecular Polymers to Induce the Targeted Protein Degradation of α-Synuclein.
  43. A novel myopathy with autophagic vacuoles associated with biallelic variants in CLN8.
  44. Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
  45. Non-canonical TLR signaling restricts cytosolic LPS detection.
  46. Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities.
  47. Lysosomes join the circular RNA decay machinery.
  48. Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
  49. Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.
  1. Autophagy. 2026 Jul 31.
    Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
    Laura Kristine Rasmussen, Diana Gomes Moreira, Justyna Okarmus, Anne Simonsen, Morten Meyer.
      Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.
    Keywords:  Autophagy receptors; E3 ubiquitin ligases; PINK-PRKN/parkin pathway; PRKN-independent mitophagy; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neurodegeneration; therapeutic targets
    DOI:  https://doi.org/10.1080/15548627.2026.2711596
  2. Membranes (Basel). 2026 Jul 06. pii: 234. [Epub ahead of print]16(7):
    A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.
    Vladimir N Uversky, Hana Popelka, Daniel J Klionsky.
      Autophagy is a carefully regulated catabolic process that utilizes assemblies of specific sets of macromolecules operating at multiple stages of the pathway. Discoveries in recent years show that autophagy markedly relies on liquid-liquid phase separation (LLPS). Here, we present parameters that indicate the plasticity of autophagy proteins and their probability to undergo LLPS in macroautophagy and microautophagy. We show that microautophagy is an extremely LLPS-friendly pathway. Several mechanisms involving proteins in the autophagy machinery that drive LLPS on various types of membranes to regulate this process or that undergo LLPS as autophagic cargo are described in detail. We also summarize the factors that modulate the LLPS potential of autophagy proteins. A high probability of autophagy-related proteins to undergo spontaneous LLPS shown here can direct future research on the role of protein droplets in autophagy.
    Keywords:  autophagy; intrinsically disordered protein; intrinsically disordered region; liquid-liquid phase separation; macroautophagy; microautophagy; posttranslational modification; protein1protein interaction
    DOI:  https://doi.org/10.3390/membranes16070234
  3. J Cell Sci. 2026 Jul 15. pii: jcs264635. [Epub ahead of print]139(14):
    Vimentin intermediate filaments support autophagosome biogenesis at ER-endosome contact sites in response to starvation.
    Quentin Frenger, Dobrawa Amiri Czajkowski, Carla Alemany, Damiana Lecoeuche, Cédric Delevoye, Etienne Morel.
      Macroautophagy (autophagy) is a fundamental catabolic process requiring the biogenesis of the autophagosome to support cell survival during stress. Although the roles of F-actin and microtubule cytoskeleton in autophagy are well established, the contribution of intermediate filaments (IFs) remains poorly understood. Here, we investigated the role of the type III IF vimentin in supporting the early steps of starvation-induced autophagy. We demonstrate that starvation triggers a rapid, perinuclear compaction of vimentin IFs, which showed enhanced overlap with the endoplasmic reticulum (ER) and correlated with transient vimentin phosphorylation at serine 56. We reveal that autophagic proteins accumulate at the vimentin-ER interface, physically connecting the autophagosome biogenesis machinery to the vimentin IF network. Knockout or pharmacological perturbation of vimentin-IFs dynamics using withaferin-A significantly impairs starvation-induced autophagic flux. Mechanistically, we reveal that vimentin IFs are essential coordinators for the mobilization of endosome-ER membrane contact sites (EERCS), a crucial hub for autophagosome nucleation. Together, our findings uncover a novel role for vimentin IFs as a dynamic cytoskeletal coordinator that spatially organizes membrane contact sites to promote the efficient initiation of autophagosome biogenesis in response to nutrient stress.
    Keywords:  Autophagosome; Autophagy; Endoplasmic reticulum; Intermediate filaments; Membrane contact sites; Vimentin
    DOI:  https://doi.org/10.1242/jcs.264635
  4. Aging Cell. 2026 Aug;25(8): e70649
    Progerin Hinders Autophagy Flux at Its Final Stages in Hutchinson-Gilford Progeria Syndrome Cells, Preventing Its Own Autophagic Degradation.
    Ian García-Aguirre, Jesús Alejandro Reyes-Martínez, Juan Unzueta, Francisco Guevara-Namorado, Solangy Lizcano-Meneses, Susana Gonzalo, Angel Baldan, Claudia Rangel, Gerardo J Alanis-Funes, Francisco Garcia-Sierra, Kevin Ruiz-Fajardo, Simon Gormes-Pinchanski, Susana Castro-Obregón, Aranza Meza-Dorantes, Rocio Alejandra Chavez-Santoscoy, Isabel Arrieta-Cruz, Paola Tristán-Aburto, Jonathan J Magaña, Bulmaro Cisneros.
      In Hutchinson-Gilford progeria syndrome (HGPS), dysfunctional autophagy results in the accumulation of progerin, a lamin A mutant variant that alters a plethora of processes, inducing senescence and driving premature aging. Therefore, the elimination of progerin through autophagy restoration emerges as a therapeutic intervention against HGPS. However, a comprehensive study of autophagy flux in HGPS remains to be addressed. In this study, the dynamics of autophagy in HGPS fibroblasts were analyzed utilizing different HGPS cell models and experimental approaches. The autophagy-associated transcriptomic profile was determined, and the autophagy-lysosome axis was comprehensively analyzed. We demonstrated that progerin induces the formation of autophagosomes but impairs their maturation and subsequent fusion with lysosomes. This alteration is attributed in part to the progerin-mediated decreased expression of STX17, a marker of mature autophagosomes, and LAMP1, a membrane lysosomal protein, as well as the presence of defective lysosomes. In line with this, the rescue of STX17 and LAMP1 expression improved autophagy flux. Interestingly, treatment of HGPS fibroblasts with Selinexor, an autophagy activator, elicited nuclear accumulation of TFEB and enhanced lysosomal biogenesis and function, thereby activating autophagy. Selinexor treatment improved both autophagosome maturation and autophagosome-lysosome fusion, which ultimately led to effective autophagic degradation of progerin. In summary, progerin impedes proper autophagy flux, thus preventing its own autophagic degradation, which underscores the relevance of targeting the autophagy-lysosome pathway to counteract the toxic accumulation of progerin.
    Keywords:  aging; autophagy; lysosomes; progeria
    DOI:  https://doi.org/10.1111/acel.70649
  5. bioRxiv. 2026 Jul 17. pii: 2026.07.15.738464. [Epub ahead of print]
    Endogenous autophagosome reporters reveal redundant and non-redundant roles of LGG-1 and LGG-2 in C. elegans neuronal autophagy.
    Heather Tsong, Mya Rodriguez, Andrea K H Stavoe.
      Autophagy is a conserved cellular recycling pathway essential for neuronal development and homeostasis. Neurons are highly polarized cells that rely on the continual turnover of cytoplasmic content through processes like autophagy to maintain cellular function. Here, we employed novel endogenous autophagosome reporters to define the distinct expression patterns, spatial distribution, and compensatory potential of the two C. elegans Atg8 orthologs, LGG-1 and LGG-2, in the nervous system. We labelled LGG-1 and LGG-2 with split wrmNeonGreen to endogenously label autophagosomes in individual neurons. We observed brighter and larger wrmNG split :LGG-1 autophagosomes relative to smaller and dimmer wrmNG split :LGG-2 autophagosomes pan-neuronally and in the individual AIY and NSM neurons. When we interrogated autophagosome trafficking in the AIY neurite, we revealed a similar trafficking mechanism for both LGG-1 and LGG-2 puncta. In AIY and pan-neuronally, we found that lgg-2 was required for LGG-1 puncta formation. Strikingly, in lgg-1 mutants, LGG-2 demonstrated a compensatory capacity in the AIY neuron via an upregulation of LGG-2 autophagosomes. Overall, our findings demonstrate the advantages of this novel endogenous reporter system for tracking neuronal autophagy and further elucidate redundant and non-redundant functions of LGG-1 and LGG-2.
    DOI:  https://doi.org/10.64898/2026.07.15.738464
  6. Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2606606123
    Spatiotemporal control of Atg2 association with the ER during autophagosome formation.
    Tetsuya Kotani, Haruki Tanabe, Shinri Kitta, Momoko Higashi, Tatsuya Niwa, Tatsuya Kaminishi, Chika Kakuta, Junko Shimasaki, Hidetaka Kosako, Tamotsu Yoshimori, Akiko Kuma, Hitoshi Nakatogawa.
      Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2-Scs2 interaction functions as a spatiotemporal switch that controls Atg2-ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.
    Keywords:  Atg2; VAP protein; autophagy; lipid transfer protein; phospho-FFAT motif
    DOI:  https://doi.org/10.1073/pnas.2606606123
  7. Science. 2026 Jul 30. 393(6810): 461
    Signatures of aging and disease in a single organelle.
    Jeeyoon Na, Anne Brunet.
      Changes in lysosomal metabolites are associated with both aging organs and lysosomal storage diseases.
    DOI:  https://doi.org/10.1126/science.aej5901
  8. Microbiol Res. 2026 Jul 28. pii: S0944-5013(26)00216-8. [Epub ahead of print]312 128652
    Host autophagy in Staphylococcus aureus infection: Mechanisms of clearance, evasion, and therapeutic intervention.
    Peng Hu, Mingyao Lu, Hillary Cassandre N'San, Ping Chen, Huiyu Liu, Yong Shi.
      Staphylococcus aureus is a facultative intracellular pathogen that persists within both professional and non-professional phagocytes, contributing to chronic and antibiotic-resistant infections. Autophagy, particularly xenophagy, serves as a central cell-autonomous defense pathway that can capture intracellular S. aureus and deliver it to lysosomes for degradation. However, the bacterium has evolved multiple strategies to subvert xenophagic clearance, including manipulation of bacteria-containing autophagosome maturation, blockade of autophagosome and lysosome fusion, and co-option of autophagy-related machinery to create intracellular survival niches. Recent studies have also identified host pathways that shape infection outcomes, including reprogramming of cell death cascades to simultaneously sustain host viability and suppress xenophagy, and co-option of mitophagy to eliminate bactericidal mitochondrial ROS. As illustrative examples, caspase-8 reprogramming uncouples host survival from effective xenophagy, and the HDAC11/IL10/mTOR/PINK1-PRKN axis drives mitophagy to suppress mitochondrial ROS. We further address the largely unexplored roles of chaperone-mediated autophagy and endosomal microautophagy in S. aureus infection, drawing on mechanistic paradigms from viral and mycobacterial infections. Since S. aureus can impair autophagosome maturation, lysosomal acidification, and fusion between bacteria-containing autophagosomes and lysosomes, enhancing autophagy initiation alone may not always translate into improved bacterial clearance. We therefore propose, as a testable hypothesis, that host-directed strategies aimed at restoring lysosomal competence, improving degradative flux, or neutralizing bacterial virulence mechanisms may complement or outperform upstream autophagy induction in selected infection contexts. However, this concept remains insufficiently validated, and direct comparative studies in relevant host cell types and animal models are needed before lysosome-directed approaches can be prioritized therapeutically.
    Keywords:  Autophagy; Chaperone-mediated autophagy; Host-pathogen interactions; Intracellular pathogen; Staphylococcus aureus; Xenophagy
    DOI:  https://doi.org/10.1016/j.micres.2026.128652
  9. bioRxiv. 2026 Jul 24. pii: 2026.07.22.740140. [Epub ahead of print]
    KIF1A-mediated trafficking is required for neuronal autophagy in human neurons.
    Carris Borland, Jacob Popolow, Erika L F Holzbaur.
      Mutations in the molecular motor protein KIF1A result in a spectrum of neurodevelopmental and neurodegenerative disorders termed KIF1A-Associated Neurological Disorder (KAND). KIF1A mutations variably disrupt synaptic vesicle trafficking, but the effects of KIF1A mutations on other trafficking pathways remain unexplored. Autophagy is a conserved pathway required for neuronal homeostasis. We investigated the role of KIF1A in autophagy using gene-edited human IPSC-derived neurons. KIF1A loss inhibited the trafficking of ATG9, a transmembrane lipid scramblase necessary for autophagosome biogenesis. This deficit significantly reduced autophagosome biogenesis and the density of axonal autophagosomes. KIF1A loss also depleted lysosomes from the axon, inhibiting autophagosome maturation. In neurons gene-edited to heterozygously express a pathogenic variant linked to a Rett-like syndrome in KAND patients, we also noted significant deficits in autophagy and lysosomal trafficking. Together, these results suggest that KIF1A-mediated transport is critical to neuronal autophagy and that deficits in autophagy may contribute to pathogenesis in KAND.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.07.22.740140
  10. Int J Mol Sci. 2026 Jul 19. pii: 6418. [Epub ahead of print]27(14):
    Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
    Chung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Hsiang-Yu Lin, Shuan-Pei Lin.
      Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
    Keywords:  Danon disease; TFEB; autophagy–lysosomal dysfunction; cardiomyopathy; gene therapy; lysosomal storage disorders; mucopolysaccharidosis
    DOI:  https://doi.org/10.3390/ijms27146418
  11. Autophagy. 2026 Jul 26. 1-16
    Transport of endo-β-mannosidase AtEBM from the cytoplasm to the vacuole through the autophagy pathway in Arabidopsis.
    Huan Wei, Jinyan Mai, Jianyu Su, Gengnan Fang, Shiting Feng, Mantao Chen, Jinxia Yu, Xiao Huang, Na Luo, Faqiang Li.
      Macroautophagy/autophagy is a conserved eukaryotic intracellular degradation pathway, with specialized forms such as the biosynthetic cytoplasm-to-vacuole targeting (Cvt) pathway in yeast, which selectively delivers several resident hydrolase precursors to the vacuole rather than for turnover. Although the core autophagy machinery is highly conserved between yeast and plants, whether autophagy plays a biosynthetic role in transporting vacuolar hydrolases in plants has remained unclear. Here, we show that Arabidopsis thaliana AtEBM (endo-β-mannosidase), a glycosidase involved in the degradation of vacuolar N-glycans, is selectively transported to the vacuole via autophagy. Further analyses revealed that AtEBM directly interacts with the core autophagy protein ATG8 through an ATG8-family interacting motif (AIM), and this interaction is essential for sequestering AtEBM into phagophores. Notably, the AIM is conserved among EBM orthologs across the green plant lineage. Phenotypic analyses of CRISPR-Cas9-generated atebm mutants revealed no defects in canonical autophagy markers (such as early senescence and nutrient starvation hypersensitivity); instead, the mutants exhibit reduced fecundity. Collectively, our findings demonstrate that AtEBM is targeted to the vacuole through a selective biosynthetic autophagy, which is functionally similar to, but molecularly distinct from the yeast Cvt pathway.Abbreviations: AIM: ATG8-family interacting motif; Ams1: α-mannosidase; Ape1: aminopeptidase I; ATG: autophagy related; Co-IP: co-immunoprecipitation; ConA: concanamycin A; Prc1/CPY: proteinase C; Cvt cytoplasm‑to‑vacuole targeting; DMSO: dimethyl sulfoxide; EE: early endosome; EBM: endo-β-mannosidase; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; FUC1: α1,3-fucosidase; GFP: green fluorescent protein; GST: glutathione S-transferase; LCI: luciferase complementation imaging; LDS: LIR-docking site; LIR: LC3-interacting region; LUC: luciferase; mAIM: mutated AIM; MS: Murashige and Skoog; MVB: multivesicular body; NBR1: next to BRCA1 gene 1; NVT: NBR1-mediated vacuolar targeting pathway; RFP: red fluorescent protein; TGN: trans-Golgi network; VPE: vacuolar processing enzyme; WT: wild-type; Y2H: yeast two-hybrid.
    Keywords:  Arabidopsis; Cvt pathway; Endo-β-mannosidase; glycosidase; selective autophagy; vacuolar hydrolase
    DOI:  https://doi.org/10.1080/15548627.2026.2706910
  12. Autophagy. 2026 Jul 30.
    Inactivation of V-ATPase induces autophagy and ectopic Notch activation to promote intestinal stem cell differentiation in adult drosophila midgut.
    Zhengran Li, Huiqing Zhao, Danjie Zhang, Jing Wei, Xiyue Tao Liu, Ruiyan Kong, Xuejing Ren, Hang Zhao, Xiaomin Fang, Jingyan Fu, Zhouhua Li.
      The self-renewal and differentiation of stem cells are tightly controlled to maintain tissue homeostasis. Failure in stem cell maintenance results in stem cell depletion and precocious aging. However, how stem cells are maintained still remains not fully understood. Here, through a large-scale RNAi screen for maintenance and proliferation of adult Drosophila intestinal stem cells (ISCs), we identify several subunits of V-ATPase including Vha68-2/ATP6V1A, required for ISC proliferation, differentiation and tissue regeneration. Inactivation of Vha68-2 results in accumulation of plasma membrane (PM)-derived structures in autophagosomes and lysosomes through Atg16 and Rab5. Furthermore, Vha68-2-defective ISCs undergo direct differentiation due to ectopic Notch activation. Mechanistically, Vha68-2 facilitates Notch receptor internalization and subsequent degradation in autolysosomes to quench ectopic Notch activation, thereby maintaining ISC fate. Truncated Notch product devoid of its extracellular domain is accumulated in autolysosomes upon Vha68-2 deficiency. The Notch products accumulated in autolysosomes still require further cleavage to drive ISC differentiation. The functions of Vha68-2 in macroautophagy/autophagy and ISC maintenance are evolutionarily conserved. Our results provide new insights into the underlying mechanism of how autophagy is involved in stem cell maintenance under physiological conditions.
    Keywords:  Autophagy; Drosophila; Rab5; Vha68-2; endocytosis; intestine; stem cell maintenance
    DOI:  https://doi.org/10.1080/15548627.2026.2711597
  13. Autophagy. 2026 Jul 31. 1-18
    Trr1 (thioredoxin reductase 1) modulates ERphagy in aging via liquid-liquid phase separation.
    Yuan Gao, Jingyi Zhao, Xiangdong Hu, Per Sunnerhagen, Beidong Liu.
      Aging is associated with the deterioration of various biological processes including disrupted proteostasis and impaired macroautophagy/autophagy. Biomolecules can undergo liquid-liquid phase separation (LLPS) to form biomolecular condensates that exert specific biological functions. Trr1 (thioredoxin reductase 1) is a pivotal enzyme in the thioredoxin antioxidant system. Deletion of TRR1 results in impaired autophagy; however, the underlying mechanism is largely unexplored. In this study, we explored whether LLPS of Trr1 affected autophagy. Trr1 formed dynamic LLPS condensates during replicative aging in yeast. Phase separation of Trr1 occurred in response to endoplasmic reticulum (ER) stress generated by cellular aging, rather than to oxidative stress. Furthermore, Trr1 condensates participated at the phagophore assembly site during endoplasmic reticulophagy and promoted autophagosome development by affecting lipidation of the Atg8 protein. Additionally, maintaining the liquid-like dynamic nature of Trr1 condensates was essential for cellular fitness. Our findings revealed an unconventional role of Trr1 through LLPS in aging. The function of phase-separated condensates of Trr1 in mitigating aging-associated ER stress offers insights into the mechanisms underlying healthy cellular aging. These findings highlight a potential target for developing interventions to combat aging and associated diseases.Abbreviations: Atg: autophagy related; DTT: dithiothreitol; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum-associated degradation; ERphagy: endoplasmic reticulophagy; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; PAS: phagophore assembly site; PLDs: prion-like domains; RFP: red fluorescent protein; RLS: replicative lifespan; Trr1: thioredoxin reductase 1; Trx: thioredoxin; UPR: unfolded protein response; IDRs: intrinsically disordered regions.
    Keywords:  Aging; ERphagy; endoplasmic reticulum stress; liquid-liquid phase separation; thioredoxin reductase 1
    DOI:  https://doi.org/10.1080/15548627.2026.2702873
  14. Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00844-2. [Epub ahead of print]45(8): 117766
    Nutrient stress activates RAB5B-mediated autophagy to remodel the synaptic proteome.
    Melina Overhoff, Lotte Ickert, Sebastian Marten, Andrew Hill, Frederik Tellkamp, Ali Chitsaz, Saskia L Ludwig, Philipp Antczak, Felix C Koehler, Roman-Ulrich Müller, Marcus Krüger, Natalia L Kononenko.
      Synaptic proteostasis is crucial for neuronal function, yet how synapses adapt to metabolic stress remains unclear. We show that nutrient stress, particularly serum withdrawal, induces autophagy-dependent remodeling of the synaptic proteome, whereas mTORC1 inhibition produces limited effects. Nutrient stress activates synaptic autophagy within 1-2 h and promotes the recruitment of the LC3 lipidation machinery via RAB5B-positive endosomal compartments in a dynein-dependent manner. Live imaging reveals enhanced RAB5B-ATG16L1 co-trafficking and increased ATG5 mobility upon serum withdrawal, indicating spatiotemporally controlled delivery of autophagy precursors to synaptic compartments. Functionally, nutrient deprivation dampens neuronal activity, while a fasting-mimicking diet induces synaptic proteome remodeling overlapping with starvation-associated autophagy cargo. In contrast, restriction of mTORC1-activating amino acids fails to induce comparable remodeling. Together, these findings identify a RAB5B-mediated trafficking pathway that links nutrient sensing to synaptic degradation, revealing how neurons maintain proteostasis under metabolic challenge.
    Keywords:  CP: metabolism; CP: neuroscience; autophagy; endosomes; nutrient stress; proteostasis; synapse; trafficking
    DOI:  https://doi.org/10.1016/j.celrep.2026.117766
  15. Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):
    Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
    Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.
      Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.
    DOI:  https://doi.org/10.1038/s41392-026-02813-2
  16. Front Cell Infect Microbiol. 2026 ;16 1843632
    The role of autophagy in protozoan infections.
    Xinlei Wang, Chao Zhang, Jie Chen, Yufen Jin, Yanan Zhang, Jingtong Zheng.
      Autophagy is a conserved, lysosome-dependent degradation system that is used by a wide variety of eukaryotes; during autophagy, intracellular substances are transported to lysosomes for degradation, and thus, autophagy plays a crucial role in cell survival under stress conditions such as starvation and hypoxia. Additionally, cells can eliminate foreign pathogens, such as parasites, bacteria, and viruses, via autophagic clearance. Protozoa are categorized as either intracellular parasitic protozoa or extracellular parasites, which are mostly zoonotic pathogens that pose significant threats to public health. In recent years, research on the mutual influences of autophagy and protozoa has focused mainly on Toxoplasma and Plasmodium, with less focus on extracellular parasitic protozoa. In this review, we discuss the crucial role of autophagy in maintaining the dynamic equilibrium between host elimination of extracellular and intracellular parasites and parasitic exploitation of the host.
    Keywords:  autophagy; host-pathogen interaction; protozoa; protozoan infections; zoonosis
    DOI:  https://doi.org/10.3389/fcimb.2026.1843632
  17. Science. 2026 Jul 30. 393(6810): eady0832
    Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    DOI:  https://doi.org/10.1126/science.ady0832
  18. bioRxiv. 2026 Jul 23. pii: 2026.07.20.739606. [Epub ahead of print]
    The tumor suppressor Tip60 inhibits TORC1 signaling in response to microbial acetate to promote autophagy and enterocyte differentiation.
    Juliana Batista, Paula I Watnick.
      The intestinal microbiota is critical for maintenance of local and systemic immune and metabolic homeostasis in animals, but few molecular mechanisms of action have been delineated. Here, using a Drosophila model, we elucidate the role of the microbial fermentation product acetate in maintenance of the intestinal barrier and enterocyte maturation. Tip60 is a lysine acetyl transferase that modifies histone and non-histone targets. We previously showed that Tip60 activates innate immune signaling in enteroendocrine cells in response to microbe-derived acetate. Here we elucidate a distinct mechanism of action in enterocytes. mTOR is a serine-threonine kinase that regulates cell growth and autophagy based on nutrient availability as part of the TORC1 complex. We report that microbe-derived acetate represses enterocyte TORC1 signaling in a Tip60-dependent manner. This licenses autophagy, which is required to destroy commensal microbes phagocytosed by enterocytes, resulting in bacterial dissemination. Single cell sequencing shows accumulation of poorly differentiated enterocytes in Tip60 knockdown intestines. The microbiota, Tip60, and mTOR have been implicated in the development and progression of colorectal cancer. As accumulation of undifferentiated precursors is a harbinger of malignant transformation and metastasis, we propose our findings provide a mechanistic link between the microbiota, Tip60, and mTOR, epithelial innate immunity and oncogenesis.
    DOI:  https://doi.org/10.64898/2026.07.20.739606
  19. Autophagy. 2026 Jul 30.
    Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction.
    Ziwen Wang, Ziyuan Zhang, Zheng Ping, Xin Zheng, Ting Wang, Zhongyong Jiang, Ge Yang, Xiaoli Zhang, Zhaochuan Liu, Bo Wu, Haimei Sun, Shu Yang, Deshan Zhou, Tingyi Sun, Xuebin Cao.
      Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.
    Keywords:  Aging; SHMT2; chaperone-mediated autophagy; collagen synthesis; fibrosis; nutritional interventions; β-hydroxybutyrate
    DOI:  https://doi.org/10.1080/15548627.2026.2711595
  20. Brain Behav Immun. 2026 Jul 30. pii: S0889-1591(26)00683-5. [Epub ahead of print] 106935
    Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.
    Pengda Li, Tao Wu, Mengjie Chen, Nan Wang, Xiaopeng Jia, Zengqiang Chen, Rui Duan.
      Aging-associated neuroinflammation is a major contributor to cognitive decline, and exercise is an effective non-pharmacological intervention against it. However, the molecular mechanisms linking peripheral adaptations to exercise with central neuroprotection in the aged brain remain incompletely understood. In this study, using aged male C57BL/6J mice subjected to 16-week treadmill exercise, we show that aerobic exercise improves cognitive function and attenuates hippocampal neuroinflammation. Through bioinformatic analysis, we identified fibroblast growth factor 21 (FGF21) as an exercise-induced yet aging-suppressed hepatokine. Notably, hepatic FGF21 knockdown eliminated the capacity of exercise to enhance hippocampal mitophagy, along with its beneficial effects on cognition and neuroinflammation. Pharmacological blockade of mitophagy recapitulated the loss of FGF21 function, similarly abolishing the exercise-induced cognitive improvements and attenuation of neuroinflammation. These findings suggest that the neuroprotective effects of FGF21 may be mediated through the promotion of mitophagy. Mechanistically, FGF21 activated the AMPK-transcription factor EB (TFEB) axis in microglia to restore lysosomal function and mitophagy. Restoration of microglial mitophagy was accompanied by reduced cytosolic mtDNA accumulation and attenuated cGAS-STING-driven neuroinflammation in the aged hippocampus. Together, our findings reveal a liver-brain axis through which exercise-induced hepatic FGF21 reshapes microglial homeostasis in the aging brain, and identify FGF21 as a potential therapeutic target for age-related cognitive decline.
    Keywords:  Aerobic exercise; FGF21; Liver-brain axis; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.bbi.2026.106935
  21. Bio Protoc. 2026 Jul 20. 16(14): e5746
    Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
    Katie G Vineall, Danielle L Schmitt.
      Phosphatase and tensin homolog-induced kinase 1 (PINK1) is a serine/threonine kinase that plays a key role in mitophagy initiation. Loss-of-function autosomal recessive mutations in PINK1 cause early onset Parkinson's disease (EOPD). Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity or provide an indirect readout of PINK1 activity. Here, we present a protocol using our newly developed phase separation-based PINK1 biosensor (PINK1-SPARK) to observe real-time activity of endogenous PINK1 in single cells. Following transfection of live cells with PINK1-SPARK, cells are treated with mitochondrial depolarizing agents and visualized using widefield or confocal fluorescence microscopy, either following the same cells over time for time-lapse imaging of PINK1 activity or end-point measurements. Thus, PINK1-SPARK is a new tool that enables the measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function. Key features • Detailed protocol for use of PINK1-SPARK, a new PINK1 biosensor introduced in Vineall et al. [1]. • PINK1-SPARK, based on phase separation, has a high signal-to-noise, enabling robust detection of PINK1 activity in multiple cell types under multiple activating conditions. • Enables measurement of real-time endogenous PINK1 activation at the single-cell level.
    Keywords:  Biosensor; Fluorescence microscopy; Functional imaging; Kinase activity reporter; Mitophagy; PINK1
    DOI:  https://doi.org/10.21769/BioProtoc.5746
  22. Nat Neurosci. 2026 Jul 29.
    Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
    Xiuli Dan, Deborah L Croteau, Wenlong Liu, Xixia Chu, Ross A McDevitt, Paul D Robbins, Vilhelm A Bohr.
      Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.
    DOI:  https://doi.org/10.1038/s41593-026-02390-1
  23. J Mol Histol. 2026 Jul 29. pii: 250. [Epub ahead of print]57(4):
    Autophagy dysfunction in pancreatic acinar cells in acute pancreatitis: from molecular mechinery and trypsinogen activation to heterogeneity and therapeutic implications.
    Yuping Feng, Wen Guo, Rui Wu, Tingting Tan, Chen Tang, Li Zhang.
      Acute pancreatitis (AP) is a common acute and critical disease of the digestive system. The initial step of its pathogenesis is the abnormal activation of trypsinogen within pancreatic acinar cells. Seminal studies have identified autophagy dysfunction as a critical upstream regulatory step in this process. Under physiological conditions, selective autophagy, such as zymophagy, may clear aberrantly activated zymogen particles in the cell and maintain pancreatic homeostasis. However, in AP defective autophagic flux, manifested by a defect in autophagosome-lysosome fusion, decreased lysosomal enzyme activity, and accumulation of microtubule-associated protein light chain 3 II (LC3-II) and sequestosome 1 (p62), induces trypsinogen missorting and premature activation. This starts the pancreatic autodigestion cascade. This results in a vicious cycle of an "autophagy pancreatic enzyme axis" involving the mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and reactive oxygen species (ROS) pathways and key regulators such as autophagy-related 16-like protein 1 (ATG16L1), vacuole membrane protein 1 (VMP1), and microRNA 155. Moreover, the mechanism of autophagy dysfunction is heterogeneous among the etiologies of AP, such as biliary, alcoholic, and hyperlipidemic acute pancreatitis. Currently, intervention strategies such as rapamycin, emodin, and miR-155 inhibitors have shown potential in regulating autophagy and reducing pancreatic injury in animal models. However, there are still challenges to clinical translation, including the target specificity, the timing of intervention, and the dual role of autophagy in AP. Future studies should focus on in-depth analysis of the mechanism of key molecules in human pancreatic tissue, development of tissue-specific autophagy regulators, and combining etiology typing and biomarkers to promote individualized treatment strategies of AP.
    Keywords:  Acute pancreatitis; Autophagy dysfunction; Autophagy-trypsin axis; Trypsinogen activation
    DOI:  https://doi.org/10.1007/s10735-026-10915-y
  24. bioRxiv. 2026 Jul 26. pii: 2026.07.22.740044. [Epub ahead of print]
    GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTS ALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE.
    Rafael M Costa, Ariane Bruder, Juliano V Alves, Debora M Cerqueira, Luis Oliveira de Moraes, Tyler Beling, Sergio Guerrero, Jaqueline Ho, Rita de Cassia A Tostes, Thiago Bruder-Nascimento.
       Background: Aldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function.
    Methods: Endothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1- activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology.
    Results: Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone.
    Conclusions: Aldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.
    DOI:  https://doi.org/10.64898/2026.07.22.740044
  25. Pharmaceutics. 2026 Jun 30. pii: 809. [Epub ahead of print]18(7):
    Nanomedicine-Mediated Autophagy Modulation in Placental Impairment Versus Cancers: A Narrative Review.
    Melinda Ildiko Mitranovici, Viviana Ivan, Adrian Apostol, Liviu Moraru, Septimiu Voidazan, Raluca Niculescu, Ioana Cristina Rotar, Florin Bobirca, Andreea Taisia Tiron, Laura Georgiana Caravia.
      The biggest challenge faced by classical anticancer therapy is drug resistance, which causes cancer recurrence and metastasis. Two underlying mechanisms could be responsible, including the stemness of pro-survival autophagy-associated cancer stem cells (CSCs). Background/Objectives: The relationship between CSCs and autophagy in gynecological cancer is still unknown. However, it has been shown that CSCs' in vitro self-renewal ability is decreased when autophagy is inhibited. Helping to maintain normal tissue homeostasis, autophagy is a catabolic process involved in degrading long-lived proteins and cytoplasmic organelles. Autophagy acts as a key player in the human body's self-regenerating tissues. It also has a reproductive function, contributing to decidualization for a successful pregnancy. The aim of our review is to identify similarities and differences between these processes, using these findings to discover new therapeutic strategies through nanotechnology. Method: We conducted a narrative review, identifying heterogeneity in the data in the literature, and found 153 relevant articles. Discussions: While autophagy has been proven to be capable of acting as a tumor suppressor, it also promotes tumor progression. Moreover, it has been linked to cancer stem cell regulation, therapy resistance, cancer invasion, and metastasis. Several molecular mechanisms have been linked to autophagy. Remarkably, some cellular processes required for proper placentation, including autophagy, are common between placental development and tumor growth. Just as trophoblast cells invade and migrate, so do cancer cells. While in the trophoblast, this phenomenon is programmed and controlled; in cancer, this regulation is lost. As shown, we thus observed commonalities and discrepancies in the phenotypes and underlying molecular mechanisms of autophagy regulation in preeclampsia versus cancer contexts. Translational applicability of nanomedicine research strategies and design paradigms between preeclampsia intervention and cancer therapy has been sought. Conclusions: Autophagy-based nanotechnology seems to be feasible in both placental ischemia in preeclampsia and cancers. This review draws parallels between targeted treatments in malignancies and placenta-derived PE. Comparing these diseases provides a novel molecular rationale and the possibility of identifying treatment through autophagy modulation.
    Keywords:  autophagy; cancer stem cells; nanotechnology; pregnancy disorders
    DOI:  https://doi.org/10.3390/pharmaceutics18070809
  26. Liver Int. 2026 Sep;46(9): e70816
    Autophagy in MASLD: A Metabolic and Precision Medicine Perspective.
    Alessandra Cazzaniga, Silvia Frigo, Alessandro Cherubini, Eniada Rrapaj, Luca Valenti.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition worldwide and a major contributor to cirrhosis and hepatocellular carcinoma (HCC). While metabolic triggers such as obesity and insulin resistance are key drivers of MASLD, growing evidence has identified defects in intracellular quality control-namely impaired autophagy-as central mechanisms governing disease progression. Autophagy, including selective lipophagy and mitophagy, plays a crucial role in hepatic lipid turnover and mitochondrial homeostasis. In MASLD, disruption of these processes contributes to lipid accumulation and oxidative stress, leading to hepatocellular damage (ballooning), fibrogenesis, and HCC. Experimental studies linked impaired autophagic flux to liver injury, and emerging evidence from human genetics suggests that inter-individual inherited variation influences MASLD susceptibility by impairing autophagy. Specifically, main genetic MASLD modifiers such as the p.I148M variant of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and loss-of-function and hypomorphic variants in autophagy-related gene 7 (ATG7), a core autophagy gene, predispose to ballooning, fibrosis, and HCC. By outlining emerging therapies that restore autophagic flux and reduce steatosis, lipotoxicity, and fibrosis, we propose an integrated precision-medicine model based on genetics and autophagy dynamics biomarkers, offering a new framework for personalized therapeutics.
    Keywords:  ATG7; PNPLA3; cirrhosis; hepatocellular carcinoma; steatosis
    DOI:  https://doi.org/10.1111/liv.70816
  27. J Cell Sci. 2026 Jul 27. pii: jcs.264719. [Epub ahead of print]
    A Golgi-bypass secretion mechanism for proTGFα involving TMED9 and GRASP65.
    Susanne S Steigleder, Isabel Döring, Marina Tauber, Julian Nüchel, Marius K Lemberg.
      We recently demonstrated that the endoplasmic reticulum export of proTGFα is tightly gated and that proteostasis factors, including the intramembrane protease RHBDL4, can promote its release by an unknown mechanism. While investigating a potential link between RHBDL4-regulated p24/TMED family proteins and proTGFα trafficking, we uncovered an RHBDL4-independent pathway in which the cargo receptor TMED9 induces unconventional protein secretion (UcPS) of ectopically expressed proTGFα. This pathway selectively requires GRASP65, but not the closely related GRASP55, and depends on components of the autophagic machinery and the ESCRT-associated protein ALIX, consistent with a Golgi-bypass secretion route. TMED9- and GRASP65-induced proTGFα secretion is insensitive to Brefeldin A treatment and involves trafficking through pre-Golgi compartments. Although largely based on overexpression systems, our findings identify a previously unrecognized UcPS mechanism and provide insight into alternative protein trafficking pathways that may be exploited under conditions of proteostasis stress and in pathological contexts such as cancer and inflammation. At present, our data establish the existence of a TMED9/GRASP65-dependent Golgi-bypass trafficking route under conditions of ectopic cargo expression, whereas its endogenous physiological relevance remains to be established.
    Keywords:  GRASP65; Golgi-bypass trafficking; Proteostasis; Secretory autophagy; TMED9; Unconventional protein secretion (UcPS)
    DOI:  https://doi.org/10.1242/jcs.264719
  28. J Cell Biol. 2026 Aug 03. pii: e202409149. [Epub ahead of print]225(8):
    PARP1 hyperactivity stalls translation and triggers stress granule formation following DNA damage.
    Maria Tereshchenko, Rebecca Earnshaw, Christopher Chin Sang, Minjung Won, Jeanine L Van Nostrand, Ryan C Russell, Hyun O Lee.
      Cells respond to various stressors by inhibiting global translation and forming stress granules (SGs), cytoplasmic organelles enriched in certain RNA-binding proteins, and RNA. Genotoxic stress also induces SG assembly, but it is unclear how nuclear stress signals are transmitted to trigger cytoplasmic responses. We show that DNA-damaging agents that activate a nuclear poly(ADP-ribose) polymerase (PARP), PARP1, stall translation and induce SGs. We find that PARP1 activation depletes NAD+, which depletes cellular ATP, activating ATP-sensor AMPK and inhibiting mTORC1 via Raptor phosphorylation. Subsequent hypophosphorylation of 4EBP1 inhibits translation. These effects are suppressed by PAR-metabolism regulators, XRCC1, PARG, and Nudix5, and reversed by NAD+ precursor supplementation. Cells lacking SG scaffolds, G3BP1 and G3BP2, show reduced viability after genotoxic stress, which is rescued by G3BP1 overexpression. These findings link PARP1 activity to translational control and SG formation, which may protect against cell death following DNA damage. These mechanisms provide insight into PARP1- and stress granule-associated diseases, including cancer and neurodegeneration.
    DOI:  https://doi.org/10.1083/jcb.202409149
  29. Nat Cell Biol. 2026 Jul 29.
    The glycolytic enzyme PGAM1 functions as a metabolic-autophagy checkpoint to coordinate growth and stress tolerance.
    Yi Zhang, Pengwei Zhao, Hangfei Liang, Zhaojie Liu, Shuling Dong, Yingcong Chen, Weijing Yao, Yuting Chen, Liting Yang, Zhonglan Shi, Lei Zhang, Yibin Pan, Fanghong Zheng, Qi Lin, Shichao Wang, Jinheng Pan, Mingzhu Fan, Shan Feng, Cheng Ma, Lifeng Pan, Ying Xing, Fan Yang, Shuiping Liu, Du Feng, Qiming Sun, Guixin Zhu, Cong Yi.
      Cell survival requires tight coordination between growth-promoting metabolism and cellular quality-control pathways, yet how these processes are integrated remains unclear. Here we identify the conserved glycolytic enzyme PGAM1 as a metabolic-autophagy checkpoint that links glycolysis to autophagy initiation independently of its catalytic activity. Using complementary yeast and mammalian systems we show that PGAM1 functions as a molecular scaffold that recruits phosphatidylinositol 3-kinase complex I to the phagophore assembly site, thereby licensing autophagosome biogenesis. This autophagy-regulatory function is genetically essential, evolutionarily conserved and functionally separable from glycolysis. It is regulated by Atg1/ULK1-mediated phosphorylation that enhances Atg14 binding under starvation. Functionally, PGAM1 coordinates anabolic growth and stress-induced survival to maintain cellular homeostasis. In cancer, PGAM1 upregulation enhances both glycolytic flux and autophagy capacity. Disruption of either function markedly impairs tumour growth, establishing PGAM1 as a homeostatic checkpoint that is hijacked in cancer to drive both proliferation and stress tolerance.
    DOI:  https://doi.org/10.1038/s41556-026-02034-3
  30. Sci Adv. 2026 Jul 31. 12(31): eaef0140
    Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
    Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.
      Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.aef0140
  31. Stem Cells. 2026 Jul 25. pii: sxag042. [Epub ahead of print]
    Vacuolar protein sorting 4B is a novel regulator of osteoblast and adipocyte differentiation by activating autophagy signaling.
    Jinyu Ma, Xingli Hu, Xinfeng Liu, Meijiao Qi, Liwen Shi, Meng Chen, Yan Xie, Baoli Wang, Jie Zhou.
      Vacuolar protein sorting 4B (VPS4B) is part of the endosomal sorting complex required for the transport (ESCRT) machinery and is essential for autophagosome completion. Vps4b mutation might reduce the ability of dental follicle cells to differentiate during the mineralization process. However, the role of VPS4B in osteogenic and adipogenic differentiation from mesenchymal stem/progenitor cells remains to be explored. In the present study, we observed a substantial presence of VPS4B in bone, as well as an increase in its expression levels during the osteogenic and adipogenic differentiation of mesenchymal progenitor cells. Functional experiments revealed that VPS4B facilitated the differentiation of both osteoblasts and adipocytes. Further mechanistic investigations revealed that VPS4B was involved in autophagy in mesenchymal progenitor cells and the positive influence of VPS4B on osteogenic and adipogenic differentiation was mitigated in the context of autophagy inhibition, indicating that the pro-osteogenic and pro-adipogenic effects of VPS4B are dependent on the autophagy signaling pathway. Our research suggests that sustaining VPS4B expression at an optimal level may be advantageous for the maintenance of bone and fat homeostasis.
    Keywords:  Vacuolar protein sorting 4B; adipocyte; autophagy; differentiation; osteoblast
    DOI:  https://doi.org/10.1093/stmcls/sxag042
  32. bioRxiv. 2026 Jul 13. pii: 2026.07.09.737487. [Epub ahead of print]
    Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
    Sambuddha Basu, Tyler G Demarest, Nicholas J Gattone, Alexandra J Gilsrud, Brittany Wicks, Apeksha Khatiwada, Mohammad Nayal, Renee Gentzel, Daniel Cohen, Eric W Kostuk, Derek P Narendra, Pedro Gonzalez-Alegre, Maria-Grazia Biferi, Elizabeth A Ramsburg.
       Background: Biallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinson's disease (EOPD). Parkin is a crucial component of PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration.
    Objective: Investigate Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD.
    Methods: We initially validated phosphorylated ubiquitin Ser65 (pUb Ser65 ) as an indicator of Parkin-mediated mitophagy initiation. We evaluated AAV-mediated PRKN replacement (hereafter, AAV-Parkin) in a Parkin knockout neuroblastoma cell line (SH-SY5Y cells) and feasibility of delivery in mouse and rat models.
    Results: Our research showed pUb Ser65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement successfully restored these pUb Ser65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid, finding Ef1a and Synapsin1 (Syn1) were most effective for transducing dopaminergic neurons in the SN of mice without causing adverse effects. These findings established a well-tolerated vector dose and an optimal capsid-promoter combination.
    Conclusions: Our results support the potential of AAV-Parkin gene therapy as a disease-modifying approach for Parkin-deficient EOPD.
    DOI:  https://doi.org/10.64898/2026.07.09.737487
  33. Curr Issues Mol Biol. 2026 Jun 23. pii: 645. [Epub ahead of print]48(7):
    Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
    Xiaobing Zhang, Huiyu Li, Jiaxin Zhao, Jiawen Tang, Xiaoqing Li, Pengjing Li, Qingyun Zhao, Qi Wang, Wei Zou.
      The second most prevalent neurodegenerative illness in the world, Parkinson's disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson's disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS-STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m6A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; m6A modification; mitochondrial malfunction; neuroinflammation; oxidative stress; therapeutic target
    DOI:  https://doi.org/10.3390/cimb48070645
  34. bioRxiv. 2026 Jul 19. pii: 2026.07.16.739079. [Epub ahead of print]
    Toxoplasma TgATG2 works with TgATG9 and TgProp1 to drive autophagic flux for parasite extracellular survival and persistence.
    Silvia Masci, Pariyamon Thaprawat, Federica Piro, Tracey L Schultz, Vern B Carruthers, Manlio Di Cristina.
      Chronic infection by Toxoplasma gondii depends on long-term survival of bradyzoites within tissue cysts, a parasite stage highly resistant to current therapies and a major barrier to eradication. Autophagy has emerged as critical pathway for bradyzoite persistence, yet the core machinery driving autophagosome formation in T. gondii remains poorly defined. Here, we identify TGME49_304630 as TgATG2, a previously uncharacterized, unusually large ATG2-like protein with conserved structural features of lipid-transfer factors. TgATG2 associates with TgATG9 and TgPROP1, key components of the parasite autophagy pathway, supporting its role in a membrane expansion complex required for autophagosome biogenesis. Using independent genetic knockouts, we show that TgATG2 is dispensable for intracellular tachyzoite replication but required for parasite fitness during extracellular stress and, most critically, for bradyzoite autophagy and viability. TgATG2 ablation disrupts autophagic activity in bradyzoites, causing progressive loss of viability and compromised cyst integrity. To overcome limitations of previous indirect assays, we developed a bradyzoite-specific dual-fluorescence TgATG8 reporter that quantitatively measures autophagic flux in T. gondii and confirmed TgATG2 as a major contributor. Importantly, TgATG2-deficient parasites are severely impaired during chronic infection in mice, with reduced brain cyst burdens, abnormal cyst morphology, and markedly diminished ex vivo bradyzoite viability. Together, these findings establish TgATG2 as a central component of the T. gondii autophagy machinery, demonstrate that autophagosome biogenesis is critical for parasite persistence in vivo, and define a molecular vulnerability and quantitative platform for targeting autophagy-dependent parasite survival.
    DOI:  https://doi.org/10.64898/2026.07.16.739079
  35. Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00817-X. [Epub ahead of print]45(8): 117739
    Human GBP4 promotes TRIM21-BIP-dependent autophagy to restrict M. tuberculosis infection by preventing SORT1-mediated progranulin degradation.
    Qinglong Guo, Jing Bi, Yu Fu, Li Song, Haojia Wu, Xi Chen, Yaqi Gong, Carl G Feng, Guoliang Zhang.
      Interferons (IFNs) are potent antimicrobial cytokines. However, effector mechanisms mediating their function in humans are poorly understood, partly because IFNs can induce numerous effector molecules. While guanylate-binding proteins (GBPs) are IFN-inducible, their role in cell-autonomous resistance to intracellular pathogens is incompletely understood. We demonstrate that human GBP1-5 significantly inhibits intracellular Mycobacterium tuberculosis (Mtb) survival, but only GBP4 mediates autophagy. GBP4 facilitates Mtb containment by promoting lysosomal acidification and autophagy via type Ⅰ IFN-dependent TFEB and FOXO3a activation. Mechanistically, GBP4 binds progranulin (GRN), reducing SORT1-mediated GRN lysosomal degradation. Moreover, GBP4 facilitates the GBP4-GRN-BIP-AKT complex assembly while inhibiting the GBP4-BIP-TRIM21 complex formation, thereby enhancing GRN-mediated BIP accumulation and AKT degradation. This leads to AKT inhibition, and concomitant TFEB and FOXO3a activation. GRN, BIP, AKT, and TRIM21 are essential for GBP4-mediated mycobactericidal activity. Our study uncovers a key role for GBP4 in regulating cell-autonomous resistance in human macrophages and may facilitate the development of host-directed therapies against tuberculosis (TB).
    Keywords:  AKT; BIP; CP: microbiology; CP: molecular biology; GRN; IFNs; Mycobacterium tuberculosis; TRIM21; autophagy flux; human GBP4; lysosomal acidification
    DOI:  https://doi.org/10.1016/j.celrep.2026.117739
  36. Drug Discov Today. 2026 Jul 27. pii: S1359-6446(26)00153-4. [Epub ahead of print] 104748
    Interplay between RNA m6A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.
    Ankita Chatterjee, Thakur Gurjeet Singh, Shareen Singh, Amritpal Kaur, Sukriti Vishwas.
      Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m6A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m6A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m6A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m6A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m6A-TG2 targeting as a promising disease-modifying approach in AD.
    Keywords:  Alzheimer’sdisease; m(6)A mRNA modification; mitophagy; neuroprotective effects; transglutaminase2
    DOI:  https://doi.org/10.1016/j.drudis.2026.104748
  37. Circ Res. 2026 Jul 31. 139(4): e329311
    TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
    Ivor J Benjamin, Jacek Zielonka.
      
    Keywords:  Editorials; heart failure; lysosomes; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329311
  38. Health Sci Rep. 2026 Aug;9(8): e72910
    Autophagy Modulation in Cancer Therapy: Navigating the Dual Roles to Overcome Chemoresistance.
    Md Mohiuddin, Md Al Mamun Ahsan.
       Background: Autophagy is a fundamental cellular recycling mechanism with complex and often opposing roles in cancer, functioning as both a tumor suppressor and a pro-survival mechanism in established tumors. This duality has attracted considerable attention, particularly regarding the therapeutic modulation of autophagy to overcome chemoresistance, a major challenge in cancer treatment. However, the function of autophagy is highly context-dependent and varies with tumor stage, cellular subpopulations, and the tumor microenvironment (TME).
    Discussion: This perspective examines the multifaceted role of autophagy in cancer, its therapeutic modulation to enhance chemosensitivity, the molecular pathways that regulate autophagy, and the current status of clinical trials with autophagy-targeting agents. We critically discuss the limitations of first-generation autophagy inhibitors, including hydroxychloroquine (HCQ) and chloroquine (CQ). Although these agents show chemosensitizing effects in some preclinical studies and have been evaluated clinically, they lack specificity and may cause off-target toxicities. Particular emphasis is placed on the emerging understanding of selective autophagy pathways, such as mitophagy and ER-phagy, and their context-dependent impact on therapeutic outcomes. We further highlight that successful autophagy-targeted therapy requires a nuanced, precision-based approach that accounts for tumor heterogeneity and microenvironmental influences and integrates advanced drug delivery strategies, including nanomedicine, to achieve spatiotemporal control of autophagy.
    Conclusion: Targeting autophagy represents a promising yet highly complex strategy for overcoming chemoresistance and requires a transition from global autophagy modulation to selective, context-specific interventions. Future research should focus on developing highly selective autophagy modulators, identifying robust predictive biomarkers, and integrating precision nanomedicine approaches to safely manage autophagy's dual roles and optimize therapeutic outcomes across diverse tumor contexts.
    Keywords:  Cancer chemosensitization; autophagy; autophagy inhibitors; autophagy modulation; chemoresistance; tumor microenvironment
    DOI:  https://doi.org/10.1002/hsr2.72910
  39. bioRxiv. 2026 Jul 20. pii: 2026.07.15.738672. [Epub ahead of print]
    Autophagy prevents ER stress-induced Tight Junction barrier disruption via claudin-2 homeostasis.
    Priya Arumugam, Kushal Saha, Ashwinkumar Subramenium Ganapathy, Alexandra Wang, Leonard Harris, Gregory Yochum, Prashant Nighot.
      Defective intestinal epithelial tight junction (TJ) barrier function and endoplasmic reticulum (ER) stress are central pathological features of inflammatory bowel disease (IBD), yet the molecular mechanisms ER stress to TJ disruption remains poorly understood. Here, we investigated the role of autophagy in regulating intestinal TJ homeostasis during ER stress. ER stress was elevated in inflamed Crohn's disease tissue and chronic dextran sulfate sodium (DSS) colitis. In human intestinal epithelial Caco-2 monolayers, murine colon, and human colonic explants, induction of ER stress with tunicamycin, thapsigargin, or brefeldin A disrupted TJ barrier integrity, as demonstrated by reduced transepithelial electrical resistance and increased paracellular permeability. ER stress selectively increased the pore-forming TJ protein claudin-2 and altered occludin localization without significantly affecting other claudins. Pharmacologic activation of autophagy with rapamycin attenuated ER stress, restored TJ barrier function, reduced claudin-2 accumulation, and preserved occludin localization. Conversely, CRISPR-Cas9-mediated deletion of autophagy gene ATG7 exacerbated ER stress, apoptosis, and TJ barrier dysfunction in vitro, while intestinal epithelial-specific Atg7 knockout mice exhibited enhanced ER stress-induced intestinal permeability in-vivo. Mechanistically, prolonged ER stress impaired autophagic flux through IRE1α kinase signaling, resulting in accumulation of p62 and claudin-2. Inhibition of IRE1α kinase activity restored autophagy, reduced claudin-2 levels, and preserved TJ barrier function. We further identified adaptor-associated kinase 1 (AAK1) as a downstream mediator of IRE1α signaling during ER stress, with increased AP2M1 phosphorylation and altered claudin-2 trafficking. Claudin-2 overexpression alone induced ER stress and lysosomal damage, suggesting a feed-forward mechanism amplifying epithelial injury. Finally, enteric rapamycin administration reduced ER stress and restored autophagy in murine DSS colitis. Collectively, these findings identify an IRE1α-AAK1-autophagy axis as a critical regulator of intestinal TJ barrier integrity during ER stress.
    DOI:  https://doi.org/10.64898/2026.07.15.738672
  40. J Cell Sci. 2026 Jul 15. pii: jcs265083. [Epub ahead of print]139(14):
    The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.
    Rebecca Morrison, Simeon R Mihaylov, Chak Hon Luk, Cyril Lemerle, Angela Rodgers, Natalia Athanasiadi, Huw R Morris, Enrica Pellegrino, Sila K Ultanir, Maximiliano G Gutierrez.
      Variants in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, yet how these variants alter immune cell function remains unclear. Because LRRK2 is activated by lysosomal damage in macrophages, we investigated how the pathogenic G2019S variant affects macrophage responses to lysosomal damage. Here, we show that LRRK2 G2019S has an effect during lysosomal damage through kinase-dependent and kinase-independent mechanisms. Phosphoproteomic analysis revealed that lysosomal damage induces selective rewiring of LRRK2-dependent Rab GTPase phosphorylation, characterised by increased Rab12 phosphorylation and reduced Rab35 phosphorylation without global kinase hyperactivation. Strikingly, LRRK2 G2019S macrophages showed increased susceptibility to apoptosis following lysosomal damage. This increase in cell death occurred independently of the kinase activity, indicating a distinct kinase-independent role of LRRK2 in regulating cell survival. We generated isogenic induced pluripotent stem cells from patients carrying the LRRK2 G2019S variant and confirmed that LRRK2 G2019S macrophages are more susceptible to cell death in a kinase-independent manner. Together, our findings support a model in which the LRRK2 G2019S variant selectively changes the phosphorylation of Rab GTPases in macrophages and increases cell death after lysosomal damage in macrophages.
    Keywords:  Apoptosis; LRRK2; Lysosomal damage; Macrophage; Parkinson's disease; Rab GTPase
    DOI:  https://doi.org/10.1242/jcs.265083
  41. Front Cell Dev Biol. 2026 ;14 1860821
    The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.
    Yao Du, Li Li, Mingtao Du, Zhi Xu, Xiaorong Zhang, Wa Cao.
      The endo-lysosomal system is a central regulator of intracellular trafficking, cargo degradation, and metabolic homeostasis. Its dynamic function is closely intertwined with lipid metabolism, forming an integrated regulatory network termed the endo-lysosomal-lipid axis. Disruption of this axis can impair endosomal maturation, lysosomal acidification, autophagic degradation, and lysosome-centered signaling pathways, resulting in defective cellular clearance and chronic inflammatory responses. Conversely, dysfunction of the endo-lysosomal system disrupts cholesterol trafficking, lipid redistribution, and macromolecular degradation, ultimately promoting secondary lipid accumulation and metabolic imbalance. In this review, we summarize the reciprocal interactions between lipid metabolism and endo-lysosomal function, with particular emphasis on membrane trafficking, lysosomal homeostasis, autophagy, membrane contact sites, and multicellular lipid clearance networks. We further discuss how these interconnected processes contribute to disease progression and highlight emerging therapeutic strategies aimed at restoring lysosomal function and lipid homeostasis. Understanding the dynamic regulation of the endo-lysosomal-lipid axis may provide new mechanistic insights into metabolic and neurodegenerative disorders and identify novel therapeutic opportunities.
    Keywords:  autophagy; cholesterol trafficking; endo-lysosomal system; endo-lysosomal–lipid axis; lipid metabolism; lysosomal dysfunction; metabolic disease
    DOI:  https://doi.org/10.3389/fcell.2026.1860821
  42. bioRxiv. 2026 Jul 23. pii: 2026.07.20.739556. [Epub ahead of print]
    Leveraging Supramolecular Polymers to Induce the Targeted Protein Degradation of α-Synuclein.
    Windfield S Swetman, Malay Mondal, Ashe M Davis, Vijay Rangachari, Tristan D Clemons.
      Halting the progression of neurodegenerative diseases remains one of the foremost challenges in medicinal chemistry due to the complex biology that drives disease progression. For example, a hallmark of synucleinopathies, such as Parkinson's disease, is the misfolding and aggregation of the protein α-Synuclein (α-Syn), driving the formation of toxic oligomers and fibrils that avoid natural intracellular clearance mechanisms, participate in unusual protein-protein interactions, and ultimately contribute to the death of dopaminergic neurons. The field of targeted protein degradation (TPD) has emerged as an innovative therapeutic route to selectively degrade proteins of interest that leverage natural intracellular protein degradation machinery. First generation TPD therapeutics have traditionally been designed as bifunctional, chimeric compounds in which a short covalent linker tethers a ligand designed to bind target proteins to a ligand that initiates an either proteosome- or lysosome-dependent protein degradation cascade. While initial studies have indicated the promise of these approaches, translation to the clinical setting has been challenging due to difficulties in achieving cellular internalization, long-term stability, and establishment of a generalizable strategy. To overcome these obstacles, this work has focused on adding modularity and dynamic capability to this classical model by leveraging a multivalent macromolecular approach to TPD. Specifically, peptide amphiphiles (PAs) were designed to self-assemble into high-aspect-ratio supramolecular nanofibers and present peptide epitopes on the surface of the fibers to target simultaneous binding of α-Syn and recruitment of enzymes that facilitate entry into the lysosome-dependent chaperone-mediated autophagy protein degradation pathway. In vitro application of these bioactive PA nanofibers has demonstrated the ability to independently internalize in cells and reduce α-Syn protein levels selectively and effectively. While further optimization of this model has the potential to be a viable therapeutic against α-Syn aggregation, the modularity of these supramolecular nanofibers through facile monomer design and incorporation illustrates the potential of establishing a platform technology for targeting a diverse range of pathologic proteins.
    DOI:  https://doi.org/10.64898/2026.07.20.739556
  43. Brain Pathol. 2026 Jul 26. e70128
    A novel myopathy with autophagic vacuoles associated with biallelic variants in CLN8.
    Ulrika Lindgren, Carola Hedberg-Oldfors, Kittichate Visuttijai, Sara Nordström, Hans Goebel, Anders Oldfors.
      Autophagic vacuoles in muscle fibers are a characteristic finding in several muscle diseases and usually indicate perturbed lysosomal protein degradation. Some of these are associated with defects in proteins directly involved in autophagy and lysosomal degradation. The gene CLN8 encodes an endoplasmic reticulum transmembrane protein, previously associated with childhood-onset neuronal ceroid lipofuscinosis (NCL), a group of lysosomal storage diseases. We describe the clinical features and results from pathology, genetic, and proteomic investigations in an adult-onset myopathy with autophagic vacuoles associated with biallelic variants in CLN8. A 40-year-old woman presented with seizures followed by transient muscle weakness and myalgia. Creatine kinase and myoglobin levels were moderately elevated. Over time, she developed progressive muscle weakness and cognitive fatigue. Muscle biopsy showed an autophagic vacuolar myopathy with fat tissue replacement and increased interstitial connective tissue. There was a marked immunohistochemical increase of markers of autophagy such as lysosomal-associated membrane protein 2 (LAMP2), microtubule-associated protein 1A/1B-light chain 3 (LC3), and sequestosome1/p62, as well as lysosomal deposition of curvilinear-like, autofluorescent material containing subunit c of mitochondrial adenosine triphosphate (ATP) synthase (mitochondrial ATP synthase membrane subunit c locus 3 [ATP5MC3/SCMAS]), typical for some forms of NCLs, including CLN8. Blood lymphocytes showed typical fingerprint inclusions. Genetic analysis revealed biallelic CLN8 variants, c.511C>T; p.P171S and c.536T>A; p.L179H. Proteomic analysis demonstrated upregulation of proteins involved in autophagy, muscle regeneration, and protein turnover. Proteins associated with oxidative phosphorylation were downregulated, except for ATP5MC3/SCMAS, which showed accumulation. In conclusion, we describe a novel myopathy with autophagic vacuoles and characteristic features of ceroid lipofuscinosis, including autophagosomal/lysosomal deposition of curvilinear-like, autofluorescent material containing ATP5MC3/SCMAS. This disease appears to be an unusual adult-onset form of CLN8.
    Keywords:  CLN8; epilepsy; myopathy; neuronal ceroid lipofuscinosis
    DOI:  https://doi.org/10.1111/bpa.70128
  44. Biomolecules. 2026 Jun 30. pii: 966. [Epub ahead of print]16(7):
    Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
    Stephen H Holland, Ricardo Carmona-Martinez, Andreas Hentschel, Alexa Derksen, Kaela O'Connor, Daniel O'Neil, Kelly Ho, Stephen D Baird, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches.
    Keywords:  GFPT1; autophagy; congenital myasthenic syndrome; glycosylation; trafficking
    DOI:  https://doi.org/10.3390/biom16070966
  45. bioRxiv. 2026 Jul 13. pii: 2025.03.10.642106. [Epub ahead of print]
    Non-canonical TLR signaling restricts cytosolic LPS detection.
    Shriram Ramani, Sara Cahill, Matthew Finnegan, Laurel Stine, Abigail Sondrini, Kiera Clayton, Liraz Shmeul-Galia, Fiachra Humphries.
      Intracellular sensing of lipopolysaccharide (LPS) is an essential component of pathogen detection that governs the innate immune response. However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.
    DOI:  https://doi.org/10.1101/2025.03.10.642106
  46. Biochim Biophys Acta Rev Cancer. 2026 Jul 25. pii: S0304-419X(26)00141-1. [Epub ahead of print] 189669
    Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities.
    Amruta Singh, Soumyadip Sinha, Prakash Kumar Senapati, Kewal Kumar Mahapatra, Sujit Kumar Bhutia.
      Lysosomes are vital organelles that maintain cellular homeostasis and orchestrate dynamic adaptations during physiological and pathological stress. Lysosomal damage, caused by various extrinsic and intrinsic factors, impairs its integrity and simultaneously disrupts the normal functioning of other organelles, including the endoplasmic reticulum and mitochondria. Lysosomal homeostasis through the lysosomal stress response (LSR) network aids cells in adapting to organelle damage, nutrient fluctuations, oxidative stress, and metabolic irregularities. This coordinated network is primarily governed by proteins, including mTOR, TFEB/TFE3, AMPK, Rag GTPases, Ragulator, and TRPML1, which integrates mechanisms involving rapid lysosomal membrane repair, selective elimination of extensively damaged lysosomes, de novo lysosomal biogenesis, and lysosomal reformation pathways. Dysregulation of the LSR network leads to different types of diseases, including cancer. This review summarizes the current understanding of lysosomal damage mitigation, particularly in cancer, where remodeling of the LSR network not only enables cancer cells to maintain metabolic plasticity by resisting therapeutic stress and promoting malignancy but also identifies the LSR network as a critical determinant in tumorigenesis. We further provide a detailed discussion of emerging evidence on the disruption of lysosomal homeostasis, highlighting strong links between lysosome-targeting drugs and cancer therapeutics. Altogether, we establish the LSR network as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.
    Keywords:  Cancer; Lysosomal damage; Lysosomal homeostasis; Lysosomal stress response (LSR) network
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189669
  47. Trends Cell Biol. 2026 Jul 30. pii: S0962-8924(26)00134-0. [Epub ahead of print]
    Lysosomes join the circular RNA decay machinery.
    Min Zhou, Hui Shen, Chuan Huang.
      Circular RNAs (circRNAs) are covalently closed, stable RNA molecules with broad physiological functions. Precise regulation of circRNA turnover is essential for cellular homeostasis. A recent study by Deng et al. uncovers an evolutionarily conserved mechanism in which RNAseK and the lysosome act synergistically to degrade circRNAs across metazoans.
    Keywords:  RNA degradation; circular RNA; endoribonuclease; lysosome
    DOI:  https://doi.org/10.1016/j.tcb.2026.07.001
  48. Antioxidants (Basel). 2026 Jun 30. pii: 830. [Epub ahead of print]15(7):
    Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
    Jingmin Che, Ye Sun, Fang Wang, Qing Feng, Cuixiang Xu, Xuhui Li.
       BACKGROUND: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.
    SCOPE OF REVIEW: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging.
    CONCLUSIONS AND IMPLICATIONS: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of "restoring mitochondrial plasticity and removing dysfunctional mitochondria", and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.
    Keywords:  age-related diseases; cellular senescence; metabolic homeostasis; mitochondrial quality control; mitophagy; therapeutic targets
    DOI:  https://doi.org/10.3390/antiox15070830
  49. Nat Cell Biol. 2026 Jul 28.
    Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.
    Nathaniel F Henneman, Genki Kawamura, Ying Luo, Catia Oliveira Dias, Jiaqi Su, Arianna Segaloni, Ivan Nemazanyy, Samuel le Cam, Calvin Rodrigues, Nicolas Kuperwasser, Nicolas Cagnard, Karim Hnia, Raphaël Margueron, Dominik Lutter, Takeaki Ozawa, Ganna Panasyuk.
      Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation.
    DOI:  https://doi.org/10.1038/s41556-026-02030-7
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