bims-auttor 2026-05-31 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–05–31
38 papers selected by
Viktor Korolchuk, Newcastle University

Characterization of a new mitophagy reporter uncovers requirement of BNIP3 for hypoxia-induced mitophagy in Drosophila.
Mammalian Lysophagy: mechanisms and pathophysiological implications.
Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.
Multifunctional Roles of Autophagy in Fungi.
Beyond cargo clearance: p62 coordinates cAMP signalling and autophagy to drive cell fate decisions in Dictyostelium discoideum.
The ubiquitin-proteasome system and autophagy as guardians of the cellular proteome.
Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
FAM134B-mediated ER-phagy degrades APP and suppresses Alzheimer's disease pathology.
Membrane ATG8ylation in secretory autophagy.
CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.
Transmembrane domain switching controls PINK1 import and fate in mitochondria.
Sequestosome-1 (p62) governs mitochondrial quality control by modulating redox homeostasis and mitochondrial dynamics in the social amoeba Dictyostelium discoideum.
NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.
Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging.
Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria.
Cell type-specific paradox of autophagy and senescence in MASH: implications for precision hepatology.
TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.
A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING.
Sestrin regulates cellular homeostasis through modulating mitochondrial function.
VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.
Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models.
Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
Unveiling C1QBP: A New Guardian of Dopaminergic Neuron in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.
Transglutaminase and its role in Alzheimer's disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics.
PRRSV NSP2 hijacks host lipophagy via a LIPE-PNPLA2-AMPK-MTOR axis to promote viral replication.
Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.
Ketogenic Diet Might Regulate Autophagy of BMSCs via mTOR Signaling Contributing to Osteoporosis in Mice.
Short-Term Combined Tat-Beclin1 and Endurance Training Improves Age-Related Decline in Physical Function in Male Mice.
OSBPL2 deficiency impaired autophagy and induced apoptosis in auditory cells via AMPK-TFEB signalling pathway.
The V-ATPase/ATG16L1 axis drives membrane remodeling during epithelial morphogenesis.
SQSTM1/p62 UFMylation Enhances Autophagic Clearance of Pathogenic Mutant Huntingtin.
p53 regulates mitochondrial function and alpha-synuclein aggregation in Parkinson's disease.
Small-molecule modulators of HIPK4 activity and proteostasis.
Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.
Carnosic acid alleviates cisplatin-induced acute kidney injury by enhancing prohibitin 2-dependent mitophagy.
Selective autophagy fine-tunes plant immunity to promote cell survival during viral infection.

Res Sq. 2026 May 11. pii: rs.3.rs-9407058. [Epub ahead of print]

Characterization of a new mitophagy reporter uncovers requirement of BNIP3 for hypoxia-induced mitophagy in Drosophila.

Hubert Osei Acheampong, Emily Rozich, Ryan Insolera.

BACKGROUND: Mitophagy is the cellular removal of unwanted mitochondria via the lysosome. Given the importance of this process to energy demanding tissues, mitophagy defects have been linked to various metabolic and neurodegenerative diseases. Mitophagy assessment tools are important for evaluating and quantifying mitophagy flux, which are useful in studying mitophagy pathways, mechanisms, and dysfunction. Mitophagy reporters are commonly used reagents to examine endpoint mitophagy flux. Following the generation of a new mitophagy reporter, mitoSRAI (mitochondrial Signal Retaining Autophagy Indicator), we introduced this reporter as a transgene into Drosophila melanogaster (Dm). We hypothesized that mitoSRAI will be capable of measuring mitophagic flux through microscopic visualization of the TOLLES:YPet fluorescence ratios, and biochemically through the relative persistence of TOLLES proteins in the lysosomes following YPet degradation.
RESULTS: We found that when we express the mitoSRAI reporter in the Dm larval muscle wall and examine mitoSRAI flux by inducing mitophagy via hypoxia, we observe a significant increase in TOLLES only fluorescent signals and bands by confocal imaging and western blotting respectively. Complementarily, the readout of mitoSRAI is sensitive to conditions of mitophagy inhibition under hypoxia. To validate our results, we compared mitoSRAI to a similarly constructed reporter, matrix-QC, and found that mitoSRAI is less responsive to neuronal and fat body mitophagy flux manipulations.
CONCLUSION: Overall, our work characterizes the strengths and weaknesses of the application of the mitoSRAI reporter in Dm. We demonstrate with the mitoSRAI reporter that BNIP3 is an important mediator for hypoxia-induced mitophagy in Dm.

DOI: https://doi.org/10.21203/rs.3.rs-9407058/v1
Autophagy. 2026 May 25.

Mammalian Lysophagy: mechanisms and pathophysiological implications.

Fujian Ji, Mingran Dai, Zimu Wang, Enyong Dai, Rui Kang, Daniel J Klionsky, Daolin Tang, Yan Huang, Yu Sun, Liu Tong.

  Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.

Keywords:  Autophagy receptor; disease; lysophagy; lysosomes; repair

DOI:  https://doi.org/10.1080/15548627.2026.2679642
Cell Rep. 2026 May 28. pii: S2211-1247(26)00541-3. [Epub ahead of print]45(6): 117463

Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.

Jing Yang, Yitian Ying, Huiwen Ye, Meiyi Chen, Xia Liu, Ganlu Wei, Jiayue She, Xinyu Lin, Muyang Wan, Xun Tan.

  Mitophagy and xenophagy, two selective autophagy pathways sharing common E3 ligases, have been proposed to intersect in host defense against invading pathogens. Here, we show that mitochondrial damage, but not mitophagy, is essential for triggering xenophagy via the inner mitochondrial membrane protein prohibitin 2 (PHB2). Upon bacteria-induced disruption of the outer mitochondrial membrane, PHB2 bridges mitochondria to bacteria by binding bacterial surface proteins, while concurrently interacting with either auto-ubiquitinated E3 ligase ARIH1 or Parkin, two well-characterized mitophagy-associated E3 ligases. This interaction positions polyubiquitin chains near PHB2-targeted bacteria to recruit selective autophagy receptors for initiating xenophagy, leading to the co-autophagic degradation of bacteria and mitochondria, a process unaffected by mitophagy inhibition. Our findings establish an uncovered mechanism of mitochondria-dependent antibacterial autophagy, positioning mitochondrial PHB2 as both a bacterial sensor and an E3 ligase scaffold, and unveiling a previously unidentified process governing the recruitment of mitophagy-associated E3 ligases to intracellular bacteria.

Keywords:  ARIH1; CP: cell biology; CP: molecular biology; Listeria; PHB2; Salmonella; Staphylococcus aureus; mitochondria; mitophagy; parkin; ubiquitin; xenophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117463
J Fungi (Basel). 2026 May 20. pii: 377. [Epub ahead of print]12(5):

Multifunctional Roles of Autophagy in Fungi.

Aron Osakina, William J Steinbach, Praveen R Juvvadi.

  Autophagy, also referred to as the "self-eating machinery", is a crucial process where organisms maintain intracellular homeostasis through recycling or degrading non-essential and damaged cellular components. It is important in numerous biological functions such as cellular differentiation, aging, nutrient sensing, stress response, tissue homeostasis, immunity, and programmed cell death. Autophagy induction occurs with the formation of a double-layered membrane structure called "autophagosome". The autophagosome wraps damaged organelles or proteins and transports them to the vacuole or lysosome for degradation. Autophagy is beneficial to organisms, and it should be optimally regulated because elevated or decreased levels are detrimental for survival. To date, more than 40 autophagy-related genes (ATGs) have been identified in the budding yeast Saccharomyces cerevisiae, with most having homologs in fungi and higher eukaryotes. Majority of the ATGs in industrial and pathogenic fungal species have been characterized and known to play vital roles in growth, development, and virulence. In this review we provide a comprehensive overview of ATGs in various fungal species and highlight how autophagy is regulated and controls various functions in plant, human, and industrial fungal species.

Keywords:  ATGs; TOR; antifungals; autophagosome; autophagy; drug resistance; fungi; golgiphagy; mitophagy; pexophagy

DOI:  https://doi.org/10.3390/jof12050377
Autophagy Rep. 2026 ;5(1): 2674406

Beyond cargo clearance: p62 coordinates cAMP signalling and autophagy to drive cell fate decisions in Dictyostelium discoideum.

Saksham Gautam, Shweta Saran.

  p62 is a multi-domain selective autophagy receptor and signaling scaffold conserved across eukaryotes. However, its evolutionary roots and functional significance in early-diverging eukaryotes like Dictyostelium have remained unexplored. In our recent study, we characterized p62 in the social amoeba Dictyostelium discoideum. Loss of p62 significantly delayed the starvation induced development and led to the formation of smaller multicellular structures. Altered p62 levels also disrupted autophagy flux and cell fate commitment in Dictyostelium cells. Treatment of p62 knockout (p62- ) cells with pulses of exogenous cyclic AMP (cAMP) partially rescued developmental defects, suggesting a potential role for p62 in sustaining intracellular cAMP levels necessary for development. Taken together, p62 emerges as an evolutionarily conserved coordinator of nutrient sensing, second messenger signaling, and autophagy that promotes multicellular development in Dictyostelium.

Keywords:  Dictyostelium; autophagy; p62 (SQSTM1); p62 cell differentiation

DOI:  https://doi.org/10.1080/27694127.2026.2674406
FEBS Lett. 2026 May 28.

The ubiquitin-proteasome system and autophagy as guardians of the cellular proteome.

Ivan Dikic.

  Maintaining a functional proteome is essential for cellular health and organismal longevity. Disruption of proteostasis is a hallmark of aging and a central driver of diverse pathologies, including neurodegeneration, cancer, and metabolic disease. The ubiquitin-proteasome system (UPS) and autophagy represent the two principal degradative pathways safeguarding proteome integrity, particularly under conditions of stress. While historically viewed as mechanistically distinct, it is now clear that UPS and autophagy operate as an interconnected and adaptive network. This Perspective discusses three core principles that govern their coordination: (1) a shared molecular language of ubiquitin signals and shuttle proteins that determines cargo routing; (2) spatial compartmentalization through organelle-specific quality control modules and phase-separated degradation hubs; and (3) temporal regulation by stress-responsive signaling pathways that reprogram proteolytic output. Understanding this dynamic partnership not only reveals fundamental organizing principles of cellular homeostasis but also identifies new therapeutic nodes for diseases driven by proteostasis collapse.

Keywords:  ER quality control; autophagy; phase separation; proteasome; proteostasis; ubiquitin

DOI:  https://doi.org/10.1002/1873-3468.70371
Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]

Mitochondria-lysosome coupling contributes to lysosome acidification and aging.

Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.

  Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.

Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification

DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
EMBO J. 2026 May 26.

FAM134B-mediated ER-phagy degrades APP and suppresses Alzheimer's disease pathology.

Yuting Zhang, Jun Sun, Yang Cai, Ziyan Xu, Xiang Li, Wei Wei, Pai Liu, Qiming Sun, Zhi-Hao Wang, Yixian Cui.

Endoplasmic reticulum autophagy (ER-phagy) is a selective autophagy pathway in which receptor proteins target ER membranes and proteins for degradation, yet its role in Alzheimer's disease (AD) remains unclear. Here, we identify FAM134B/RETREG1 as a specific ER-phagy receptor mediating amyloid precursor protein (APP) degradation. FAM134B directly interacts with ER-localized wild-type and familial mutant APP via their C-terminal domains and recruits LC3 through its LC3-interacting region (LIR) to promote APP delivery to phagophores for lysosomal degradation. In AD, epigenetic silencing at the FAM134B promoter suppresses its transcription by limiting TFEB/TFE3 binding despite their nuclear enrichment. This transcriptional suppression impairs ER-phagy, leading to APP accumulation and exacerbated AD pathology. AAV-mediated hippocampal expression of wild-type, but not LIR-mutant, FAM134B in 5XFAD mice restores ER-phagy, enhances APP clearance, reduces Aβ deposition, preserves synaptic and myelin integrity, and improves cognitive performance. These findings establish FAM134B downregulation as an upstream pathogenic event in AD, suggesting ER-phagy enhancement as a promising strategy to suppress Aβ generation at its source.

DOI: https://doi.org/10.1038/s44318-026-00818-9
Autophagy. 2026 May 24. 1-16

Membrane ATG8ylation in secretory autophagy.

Jayanta Debnath, Andrew M Leidal.

  Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.

Keywords:  ATG8ylation; extracellular vesicles and particles; noncanonical autophagy; secretory autophagy; unconventional protein secretion

DOI:  https://doi.org/10.1080/15548627.2026.2676796
Autophagy. 2026 May 25.

CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.

Zhou Wei, Maggie Zhang, Willcyn Tang, Brijesh Kumar Singh, Zhang Zhiwei, Zhou Lei, Jaron Goh Kim Wee, Faith Tan Rui En, Huang Jingxiu, Sun Qiaoyang, Xiao Bin, Gupta Priyanka, Alfred Sun Xuyang, Zeng Li, Shen Han-Ming, Tan Eng King.

  Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of CHCHD2, and also in human iPSC-derived CHCHD2-/- or CHCHD2T61I dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.

Keywords:  Aggregates; CHCHD10; CHCHD2; GABARAPs; autophagy; neurodegeneration

DOI:  https://doi.org/10.1080/15548627.2026.2678427
EMBO J. 2026 May 26.

Transmembrane domain switching controls PINK1 import and fate in mitochondria.

James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.

DOI: https://doi.org/10.1038/s44318-026-00789-x
Microbiol Res. 2026 May 26. pii: S0944-5013(26)00128-X. [Epub ahead of print]310 128564

Sequestosome-1 (p62) governs mitochondrial quality control by modulating redox homeostasis and mitochondrial dynamics in the social amoeba Dictyostelium discoideum.

Saksham Gautam, Shweta Saran.

  Sequestosome-1 (SQSTM1/p62) is a multifunctional scaffold protein that links autophagy, proteasomal degradation, and redox signalling, but its mitochondrial functions in lower eukaryotes remains unclear. Using p62 mutant strains of the protist, Dictyostelium discoideum, we demonstrate that p62 is a critical regulator of mitochondrial integrity and oxidative stress tolerance. Loss of p62 reduced cell survival during starvation and elevated oxidative stress, as evidenced by the increased proportion of DHE-positive cells, enhanced MitoSOX fluorescence, and nearly 40% reduction in mitochondrial membrane potential. Mitochondrial network analysis revealed a fragmented mitochondrial architecture in p62⁻ cells, consistent with a fission-dominated dynamics as quantified by live-cell time-lapse confocal microscopy. Overexpression of p62, restored redox balance, upregulated antioxidant enzyme activities (SOD and GST), and shifted mitochondrial dynamics towards fusion, resulting in mitochondrial elongation and network formation. Notably, p62⁻ cells were also characterised by increased basal and starvation-induced mitophagy that persisted despite canonical autophagy modulation, suggesting the involvement of a non-canonical, Atg8-independent mechanism. Collectively, these findings reveal a conserved role for p62 in governing mitochondrial quality control by modulating redox homeostasis and mitochondrial dynamics.

Keywords:  Dictyostelium; Mitochondrial dynamics; Mitophagy; P62/SQSTM1; Redox homeostasis

DOI:  https://doi.org/10.1016/j.micres.2026.128564
Autophagy. 2026 May 24. 1-19

NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.

Jie Cui, Shifeng Ren, Bingjie Wang, Nan Zhang, Shanshan Zhu, Yajun Zhang, Xiangqing Qi, Weixue Meng, Liwei Shao, Shan Gao, Lijie Xing, Zengjun Li, Xiaodong Mu.

  The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.

Keywords:  Cellular senescence; cytoskeleton; innate immunity; mechanical stress; mitochondrial damage; mitophagy dysfunction

DOI:  https://doi.org/10.1080/15548627.2026.2677181
Mol Cell. 2026 May 29. pii: S1097-2765(26)00311-4. [Epub ahead of print]

A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.

Marine Berquez, Alexander L Li, Matthew A Luy, Anthony C Venida, Simon McDowall, Thomas O'Loughlin, Gilles Rademaker, Abhilash Barpanda, Jingjie Hu, Julian Yano, Arun P Wiita, Luke A Gilbert, Peter M Bruno, Rushika M Perera.

  Pancreatic ductal adenocarcinoma (PDAC) evades immune surveillance in part through autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I), though the basis for this vulnerability is unclear. Using synchronized endoplasmic reticulum (ER) exit assays, we show that PDAC cells retain MHC-I in the ER and inefficiently traffic it to the plasma membrane. We identify an autophagic capture complex composed of the ER-phagy receptor TEX264 and the cargo receptor NBR1 that targets MHC-I for degradation. Suppression of either receptor restores total and surface MHC-I levels. Capture is linked to antigen loading, as impaired peptide loading increases MHC-I binding to the TEX264-NBR1 complex, while high-affinity peptides reduce binding and promote increased surface localization. A genome-wide CRISPRi screen identified the ER-localized E3 ligase NFXL1 as a mediator of MHC-I ubiquitylation and capture. Elevated NFXL1 correlates with reduced MHC-I expression and poor prognosis, highlighting a targetable pathway regulating PDAC immunogenicity.

Keywords:  ER-phagy; MHC-I; autophagy; lysosome; pancreatic cancer

DOI:  https://doi.org/10.1016/j.molcel.2026.05.005
NPJ Aging. 2026 May 26.

Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging.

Beatriz Escobar-Doncel, Xiaoyi Zhang, Åsne Ljøstad, Mario Fernández de la Puebla, Shreyas Balachandra Rao, Synnøve Algrøy Fjeldstad, Maja Tvedt Dahle, Mahmood Amiry-Moghaddam, Magnar Bjørås, Evandro Fei Fang, Wannan Tang.

Mitochondrial homeostasis is majorly maintained through mitochondrial autophagy (mitophagy). Recent research highlights the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving male mice across two age groups, including 2-3-month-old (early-aged) and 18-20-month-old (old-aged) mice. We show reduced mitophagy in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons at the same age, in both age groups. Pharmacological augmentation of NAD+, a pivotal metabolite that induces mitophagy but normally declines in the aging brain, increased cellular mitophagy in both neurons and astrocytes in old-aged male mice at the dose and method of administration tested. Collectively, our data support an age-dependent reduction of mitophagy in neurons and astrocytes, at least in mouse somatosensory cortex, while NAD+ repletion offsets such reduction.

DOI: https://doi.org/10.1038/s41514-026-00414-5
Autophagy. 2026 May 25.

Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria.

Yanglin Wu, Tingting Fu, Yun Teng, Ying Pan, L Li, Yu Feng, Jun Lin.

  Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Numerous clinical studies have revealed that exercise is extremely beneficial for the outcome of RA. However, the underlying mechanism remains poorly understood. In the present study, we investigated the therapeutic efficacy of irisin, an exercise hormone, on K/BxN serum and collagen-induced arthritis (CIA), two well established mouse models for RA research. Mechanistically, irisin interacted with ITGAV (integrin subunit alpha V) and ITGB5 (integrin subunit beta 5) to activate mitophagy and remove leaked mitochondrial DNA (mtDNA) and reactive oxygen species (ROS), which suppressed the activation of NLRP3 (NLR family pyrin domain containing 3) inflammasome and then hindered the pathological process of experimental arthritis. Notably, the beneficial effects of irisin on the treatment of experimental arthritis were significantly abolished in mice with atg5 (autophagy related 5) conditional knockout in myeloid cells (atg5fl/flLyz2). Our study elucidated the underlying mechanism through which exercise alleviated experimental arthritis and offered a feasible therapeutic strategy for RA.

Keywords:  Experimental arthritis; NLRP3 inflammasome; irisin; mitophagy; rheumatoid arthritis

DOI:  https://doi.org/10.1080/15548627.2026.2680560
Front Cell Dev Biol. 2026 ;14 1837383

Cell type-specific paradox of autophagy and senescence in MASH: implications for precision hepatology.

Md Entaz Bahar, Deok Ryong Kim.



Keywords:  MASH; autophagy; hepatic stellate cells; hepatocytes; senescence

DOI:  https://doi.org/10.3389/fcell.2026.1837383
Free Radic Biol Med. 2026 May 28. pii: S0891-5849(26)00828-2. [Epub ahead of print]

TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.

Zhiqiang Li, Yuxiang Tang, Dongyuan Zhang, Jiayi Li, Tianxiang Wang, Qiuxia Pan, Xianbin Meng, Xiaolin Tian, Haiteng Deng.

  Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) level, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.

Keywords:  Autophagy; Microglial Senescence; PI3K/AKT/mTORC1 Pathway; Transglutaminase2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.324
bioRxiv. 2026 May 13. pii: 2026.05.11.724378. [Epub ahead of print]

PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.

Julia F Riley, Charity V Robbins, Erika L F Holzbaur.

Astrocytes directly influence neuronal survival and increasingly are understood to contribute to the progression of neurodegenerative diseases including Parkinson's disease (PD). Mitochondrial damage is a hallmark of PD pathology in both neurons and astrocytes. Damaged mitochondria are cleared by PINK1/Parkin-mediated mitophagy; loss-of-function mutations in either PINK1 or Parkin are sufficient to cause PD. Neuronal mitophagy is well-studied, but far less is known about how mitochondrial dysfunction in astrocytes affects neural health. While microglial release of pro-inflammatory cytokines has been shown to induce astrocytes to mount their own inflammatory response, we hypothesize that a more direct pathway is involved, and that mitochondrial damage to astrocytes directly triggers release of proinflammatory cytokines. To address these questions, we treated primary murine cortical astrocytes with oxidative phosphorylation (OXPHOS) inhibitors antimycin A (AA) and oligomycin A (OA) and observed the PINK1-dependent accumulation of Parkin on damaged mitochondria, leading to phospho-ubiquitination of proteins in the outer mitochondrial membrane and the recruitment of the autophagy receptor SQSTM1/p62. To identify transcriptional changes caused by mitochondrial damage and the resulting activation of mitophagic machinery, we performed bulk RNA-sequencing on astrocytes isolated from WT, PINK1 -/- , or Parkin -/- mice treated with AA/OA or a vehicle control. In WT astrocytes, TNF-α signaling via NF-κB was the most significantly upregulated pathway following OXPHOS inhibition. OXPHOS inhibitor treatment also stimulated p62 expression, while NF-κB inhibition prevented this upregulation. Astrocytic secretion of cytokines, including TNF-α, was increased following mitochondrial damage; this secretion was dependent on NF-κB activation and occurred at levels sufficient to induce mitochondrial depolarization in hippocampal neurons. Compared to WT astrocytes, PINK1 -/- astrocytes showed a significant reduction in transcriptional signatures associated with TNF-α signaling following mitochondrial damage, while Parkin -/- astrocytes exhibited upregulation of both IFN-γ and IFN-α signaling. These findings indicate altered inflammatory responses to mitochondrial damage in the absence of functional PINK1 or Parkin. Finally, we analyzed scRNA-sequencing data from substantia nigra astrocytes harvested from human brain tissue from PD-positive or control samples. Distinct clusters comprised predominantly of PD-positive or control astrocytes emerged. Astrocytes in the PD-positive cluster were enriched for NF-κB, IFN-α and IFN-γ responses, consistent with the signaling observed in vitro post-OXPHOS inhibition. Together, these findings identify inflammatory signatures activated by mitochondrial damage in astrocytes, and establish this pathway as a potential contributor to neuroinflammation in PD.

DOI: https://doi.org/10.64898/2026.05.11.724378
Nat Commun. 2026 May 27. pii: 4602. [Epub ahead of print]17(1):

A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING.

Tsumugi Shoji, Ayumi Shinojima, Takuma Kishimoto, Kanako Sato, Nana Ikegami, Eisuke Yumoto, Ruri Shindo, Yasunori Uchida, Satoshi Kusumi, Daisuke Koga, Eiji Yamamoto, Yoshinori Hirano, Ryo Ogino, Hirofumi Shibata, Kazushi Izawa, Takahiro Yasumi, Ryota Sato, Jun Nakayama, Shigeki Higashiyama, Junya Hasegawa, Hiroaki Kajiho, Takehiko Sasaki, Yoshihiko Kuchitsu, Tomohiko Taguchi.

Stimulator of interferon genes (STING) is critical for the type I interferon responses to pathogen- or self-derived cytosolic DNA. STING signalling is terminated by ESCRT-driven lysosomal microautophagy. How STING is directly encapsulated by lysosomes has not yet been understood. Here we show that two lysosomal components, a phosphoinositide PI(3,5)P2 and CHMP4B (a subunit of ESCRT-III subcomplex) are essential for STING encapsulation by lysosomes. Liposome sedimentation assay reveals that CHMP4B binds to PI(3,5)P2. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P2) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P2, cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of Chmp4b. Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane.

DOI: https://doi.org/10.1038/s41467-026-72828-4
FEBS J. 2026 May 27.

Sestrin regulates cellular homeostasis through modulating mitochondrial function.

Alexander Haidurov, Andrei Budanov.

  For years, the function of Sestrin proteins has been assigned to antioxidant protection and regulation of mTOR complexes 1 and 2. However, recent data demonstrate that Sestrins have a new role in the regulation of mitochondrial functions through incompletely understood mechanisms. These include Sestrin involvement in the control of mitochondrial biogenesis, respiration and mitophagy. Machado et al. describe a key role of Sestrin2 in the regulation of mitochondrial function in myoblast C2C12 cells. Sestrin2 supports mitochondrial biogenesis and respiration through control of mitochondrial protein expression and tuning up mitophagy. These discoveries expand our understanding of the potential role of Sestrins in supporting muscle function through mitochondrial signalling.

Keywords:  ageing; mTOR; mitochondria; myoblasts; sestrin

DOI:  https://doi.org/10.1111/febs.70604
Acta Neuropathol Commun. 2026 May 29.

VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.

Priyanka Tripathi, Haihong Guo, Alfred Yamoah, Ramkumar Mathur, Panagiotis Doukas, Alice Dreser, Christopher Marvin Jesse, Eleonora Aronica, Andreas Hermann, Harry Steinbusch, Gary Anthony Brook, Joachim Weis, Anand Goswami.

  During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.

Keywords:  ALS8; Autophagy; RBPs; Selective MN vulnerability; VAPB

DOI:  https://doi.org/10.1186/s40478-026-02298-8
Aging Cell. 2026 Jun;25(6): e70566

Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models.

Tariq T Ali, Anton Zhornyak, Madiha Merghani, Zora Buschenlange, Eri Sakata, Tiago F Outeiro, Blagovesta Popova, Gerhard H Braus.

  Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the aggregation of alpha-synuclein (αSyn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of αSyn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin-proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of αSyn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The αSyn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on αSyn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces αSyn aggregation and enhances αSyn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric αSyn in vitro. Notably, capped proteasomes retain proteolytic activities in the presence of αSyn, indicating resistance to αSyn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulators of αSyn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of αSyn toxicity.

Keywords:  20S proteasome; Parkinson disease; alpha‐synuclein; autophagy; posttranslational modifications; proteasomal chaperones; protein homeostasis; yeast

DOI:  https://doi.org/10.1111/acel.70566
Nat Commun. 2026 May 26.

Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.

Kritarth Singh, Hormos Salimi Dafsari, Olivia Gillham, Haoyu Chi, Ivet Mandzhukova, Ioanna Kourouzidou, Preethi Sheshadri, Chih-Yao Chung, Valeria Pingitore, Fleur Vansenne, David L Selwood, Diana Pendin, Gyorgy Szabadkai, Manolis Fanto, Heinz Jungbluth, Michael R Duchen.

The autophagy-tethering factor ectopic P-granule 5 autophagy protein (EPG5) plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 causes a rare devastating multisystem disorder known as Vici syndrome, which features neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are only partially understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we find that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological cytosolic Ca2+ transients result in unexpected mitochondrial Ca2+ overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca2+ signals cause mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we identify a pathophysiological cascade driving disease progression associated with EPG5 deficiency, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-73538-7
Free Radic Biol Med. 2026 May 22. pii: S0891-5849(26)00784-7. [Epub ahead of print]

Unveiling C1QBP: A New Guardian of Dopaminergic Neuron in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.

Jing Li, Yihan Wang, Min Liu, Zhenlong Yu, Yan Wang, Peng Wang, Cong Guo, Minzhi Wang, Ruifeng Shi, Yulin Peng, Jing Tan, Yongzhong Lin.

  Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding protein (C1QBP) plays a crucial role in regulating mitophagy and maintaining mitochondrial homeostasis. This study aims to investigate the role of C1QBP in the pathogenesis of PD by employing bidirectional modulation of C1QBP expression in the PD models. Our results showed reduced C1QBP expression in PD models. C1QBP deficiency aggravated motor dysfunction and dopaminergic neuron degeneration induced by MPTP, while its overexpression exerts protective effects. Mechanistically, C1QBP ameliorates MPP+-induced mitochondrial dysfunction, thereby attenuating neuronal loss. Furthermore, C1QBP promotes mitophagy to maintain mitochondrial homeostasis in PD models. However, these neuroprotective effects of C1QBP were abolished upon UNC-51-Like Kinase 1 (ULK1) knockdown. Collectively, our study has identified C1QBP as a novel guardian for dopaminergic neurons in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.

Keywords:  C1QBP; Parkinson’s disease; ULK1; mitochondrial function; mitophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.304
Geroscience. 2026 May 25.

Transglutaminase and its role in Alzheimer's disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics.

Samson Prince Hiruthyaswamy, Dinesh Rao, Sreeja Balakrishna, Nazarene Marylene Nicky Macarius, Yukesh Kumar Sakthivel, Kanagavel Deepankumar, Murali Vijayan.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline driven by amyloid-β plaques, tau neurofibrillary tangles, and extensive neuronal loss. Emerging evidence highlights mitochondrial dysfunction, defective mitophagy, and disrupted proteostasis as pivotal events in disease progression. Transglutaminase TG2, a multifunctional calcium-dependent enzyme, has gained attention for its capacity to link these pathological processes. Beyond catalyzing ε-(γ-glutamyl)-lysine crosslinks that stabilize amyloid and tau aggregates, TG2 interacts with mitochondrial membranes, altering permeability and bioenergetic efficiency. In neurons, aberrant TG2 activity promotes oxidative stress, impairs mitophagy through crosslinking of PINK1 and Parkin, and exacerbates calcium dyshomeostasis via modification of VDAC and ANT1, culminating in energy failure and apoptosis. Aging-related increases in ROS and inflammatory cytokines further amplify TG2 activation, reinforcing proteostatic collapse and synaptic degeneration. Recent metabolomic studies reveal that TG2-mediated dysregulation extends to lipid and amino acid metabolism, affecting mitochondrial respiration and neuronal signaling. Therapeutically, selective TG2 inhibition restores autophagic flux, mitigates mitochondrial damage, and reduces aggregate burden in preclinical models. This integrative review underscores TG2 as a central orchestrator connecting mitochondrial dysfunction, aging, mitophagy failure, and metabolic imbalance in AD. Targeting TG2's transamidase activity while preserving its regulatory roles may offer a promising strategy for neuroprotection and disease modification.

Keywords:  Alzheimer’s disease (AD); Metabolomics; Mitochondrial dysfunction; Mitophagy; Synaptic degeneration; Transglutaminase 2 (TG2)

DOI:  https://doi.org/10.1007/s11357-026-02320-w
Autophagy. 2026 May 27. 1-27

PRRSV NSP2 hijacks host lipophagy via a LIPE-PNPLA2-AMPK-MTOR axis to promote viral replication.

Zhenbang Zhu, Qianwen Lin, Xinyu Zhang, Meng Zhang, Yifan Yan, Wenqiang Wang, Wei Wen, Xiangdong Li.

  Porcine reproductive and respiratory syndrome virus (PRRSV) exploits host lipid metabolism to support its replication by harnessing lipids and their metabolic derivatives. Lipophagy, a selective autophagic process responsible for lipid droplet (LD) degradation and cellular lipid homeostasis regulation, has been implicated in viral infections, however, its specific role in PRRSV replication has not been investigated. In this study, we found that PRRSV infection triggered lipophagy, resulting in LD depletion and elevated intracellular free fatty acids. Mechanistically, the viral protein NSP2 was essential for PRRSV-induced lipophagy by directly interacting with LD-associated lipases LIPE and PNPLA2, facilitating their binding to MAP1LC3/LC3 via LIR motifs. Both interactions were required for lipophagy-dependent viral replication. Furthermore, we demonstrated that the AMPK signaling pathway critically regulated PRRSV-induced lipophagy. AMPK activation promoted viral replication, whereas its inhibition impaired both lipophagy and viral propagation. Conversely, MTOR signaling acted as a negative regulator of lipophagy, with MTOR inhibition promoting this process. Collectively, these findings established that PRRSV hijacked host lipophagy to facilitate viral replication through NSP2-LIPE-PNPLA2 interactions and an AMPK-MTOR signaling pathway. Our work provided mechanistic insights into viral pathogenesis and highlighted potential therapeutic targets for PRRSV prevention and control.Abbreviations: AMPK: AMP-activated protein kinase; co-IP: co-immunoprecipitation; CQ: chloroquine; CMA: chaperone-mediated autophagy; FFA: free fatty acid; HEK-293T: human embryonic kidney 293T; hpi: hour post infection; LAMP1: lysosome associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lipase A, lysosomal acid type; LIPE/HSL: lipase E, hormone sensitive type; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGLL: monoglyceride lipase; MG132: carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NSPs: non-structural proteins; ORFs: open reading frames; PNPLA2/ATGL: patatin-like domain 2, triacylglycerol lipase; PRRSV: porcine reproductive and respiratory syndrome virus; SQSTM1/p62: sequestosome 1.

Keywords:  Autophagy; NSP2; PRRSV; lipid droplet; lipophagy; replication

DOI:  https://doi.org/10.1080/15548627.2026.2676077
bioRxiv. 2026 May 13. pii: 2026.05.12.724612. [Epub ahead of print]

Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.

Jasmin S Revanna, Karl Wessendorf-Rodriguez, Qiang Xiao, Thais S Sabedot, Michael S Cuoco, Snigdha Sarkar, Lucia Zhou-Yang, Christina K Lim, Victoria N Prozapas, Rowan S Wooldridge, Jean Paul Chadarevian, Joshua M Pratt, Sheila C Steiner, Ava Katz, Jerome Mertens, Jeffery W Kelly, Santiago Solé-Domènech, John T Melchior, Christian M Metallo, Jeffrey R Jones, Fred H Gage.

While Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for late-onset Alzheimer's disease, its mechanistic role in the brain-resident macrophage, microglia, remains elusive. Microglia are important in the clearance of pathology in disease, heavily relying on lysosome functionality; therefore, we sought to understand the impact of APOE4 on microglial function. APOE44 microglia have been shown to have lipid accumulation, yet the mechanisms leading to this accumulation are unknown. Using induced pluripotent stem cell-derived microglia, we found that the APOE4 haplotype resulted in transcriptional state shifts in microglia, suppressing activated-response microglia (ARMs) and promoting a G2 senescent-like state. We found that APOE44 microglia accumulate cholesterol esters and provide less lipid support to fibroblast-induced neurons, decreasing their synaptic connections. APOE44 microglia secrete significantly less lipoproteins, leading to the accumulation of lipoproteins within the cells including the lysosomes. APOE44 microglia exhibit impaired lysosomal acidification and degradation capacity. Further, our results elucidated that APOE44 microglia are proinflammatory and shift away from fatty acid oxidation towards glycolysis, due to dysfunctional mitochondria. Taken together, our findings indicate that a loss-of-function in lipoprotein secretion drives intracellular lipid accumulation, including within lysosomes, ultimately disrupting the lysosome-endoplasmic reticulum-mitochondrial axis. This drives a proinflammatory and metabolically compromised microglial phenotype with impaired neuro-supportive functions.
GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.64898/2026.05.12.724612
FASEB J. 2026 May 31. 40(10): e71890

Ketogenic Diet Might Regulate Autophagy of BMSCs via mTOR Signaling Contributing to Osteoporosis in Mice.

Qi Liu, Zhou Yang, Yongnong Ye, Ruo Yao Li, Xinjun Fan, Haoshan Lin, Yutao Wang, Xiuhua Wu, Qingan Zhu.

  Rapamycin (Rapa), an mTOR inhibitor, enhances autophagy to alleviate bone loss in senile and estrogen-deficient osteoporosis by restoring the biological properties of bone marrow stromal cells (BMSCs). However, Rapa against bone loss induced by ketogenic diet (KD) and the underlying mechanism remain elusive. This study aims to evaluate Rapa's influence on KD-induced osteoporosis and clarify its underlying mechanisms. Microarchitectures of bone, serum concentrations of bone alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), along with osteocalcin (OCN), microtubule-associated protein light chain 3 (LC3), TRAP, and Sca-1 immunohistochemistry staining were evaluated in Sham, the OVX (ovariectomy), the OVX+ Rapa, the KD, and the KD+ Rapa groups. Expression of mTOR and the autophagy-related proteins, including LC3-II/LC3-I, Beclin1, ATG7, and P62 were also analyzed. Both KD and OVX induced significant bone loss in the cancellous bone of the distal femur and the L5 vertebra. Furthermore, KD effectively decreased serum ALP and increased TRAP in mice. In addition, KD and OVX downregulated OCN, ALP, RUNX2, the autophagy-related proteins, upregulated TRAP, PPARγ, p-mTOR, and P62, and decreased LC3 and Sca-1 expressions in mice. On the other hand, Rapa reduced significant bone loss in cancellous bone induced by KD or OVX. Additionally, Rapa effectively increased serum ALP and decreased TRAP in KD mice and decreased serum TRAP in OVX mice. It upregulated OCN, ALP, RUNX2, LC3-II/LC3-I, Beclin1, and ATG7 and downregulated TRAP, PPARγ, p-mTOR, and P62 in the KD and OVX cohorts. The findings demonstrated that autophagy downregulation might contribute to KD-induced osteoporosis, which may be part of the pathogenic mechanism responsible for bone loss during KD.

Keywords:  autophagy; ketogenic diet; mTOR; osteoporosis; rapamycin

DOI:  https://doi.org/10.1096/fj.202601131R
bioRxiv. 2026 May 12. pii: 2026.05.07.723527. [Epub ahead of print]

Short-Term Combined Tat-Beclin1 and Endurance Training Improves Age-Related Decline in Physical Function in Male Mice.

Thuan Thien Tchen, Shakibur Rahman, Thaysa Ghiarone, Lynn A Spruce, Hossein Fazelina, Elizabeth M Brown, Charalampos Papachristou, Sue C Bodine, Vitor A Lira, Kleiton A S Silva.

Autophagy is a hallmark of aging, but autophagy-related proteins have not been exclusively targeted to attenuate the progressive decline in physical function associated with aging. Here, we combined Tat-Beclin1, an autophagy agonist, and endurance training to determine whether Tat-Beclin1 enhances exercise adaptation in old male mice. Tat-Beclin1 was administered intraperitoneally (TB group, 15 mg/kg, 2x/week) as a standalone therapy, or in combination with endurance training (TB+Exe group, 70% of maximal running speed 3x/week) for 1 month in 23-month-old male C57BL/6J mice. Control groups were age-matched cage controls and exercise-only groups. Animals were assessed for grip strength, endurance capacity on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). TB+Exe led to significant increases in grip strength, endurance capacity, and balance and coordination performance beyond those observed in the TB and Exe groups alone. Autophagy markers, including Beclin1, the LC3B-II/I ratio, and p62, did not differ among groups. A proteomic analysis of the G/P muscle revealed that TB upregulated biological processes involved in muscle contraction and adaptation, whereas TB+Exe increased mitochondrial bioenergetic processes and, surprisingly, upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. We conclude that combining Tat-Beclin1 and endurance training may represent a new approach to attenuate aging-related decline in physical function.
New & Noteworthy: We show evidence that combining Tat-Beclin1 and endurance training (TB+Exe) resulted in greater improvements in physical function in 24-month-old male mice than either standalone therapy. We also show that TB+Exe upregulates traditional exercise-like biological processes and unexpectedly upregulates acute-inflammatory proteins (e.g., orosomucoid-1), which are thought to improve physical function in preclinical studies. Our study suggests that TB may be a new drug enhancing physical function, especially when combined with endurance training in old male mice.

DOI: https://doi.org/10.64898/2026.05.07.723527
Cell Signal. 2026 May 25. pii: S0898-6568(26)00272-X. [Epub ahead of print]145 112619

OSBPL2 deficiency impaired autophagy and induced apoptosis in auditory cells via AMPK-TFEB signalling pathway.

Xiaoyang Wang, Tianqi Li, Jinglei Jiang, Yajie Lu, Zhibin Chen, Xiuhong Pang, Guangqian Xing, Xin Cao, Qinjun Wei, Jun Yao.

  OSBPL2 was identified as a causal gene responsible for autosomal dominant non-syndromic hearing loss. Previous study revealed that OSBPL2-mediated AMPK signalling was crucial for cholesterol-homeostasis in inner ear. AMPK is the downstream component of a kinase cascade as the key regulator of autophagy, metabolism, cell growth and apoptosis, etc. In addition, OSBPL2 deficiency could lead to autophagy impairment in auditory cells, indicating the potential role of OSBPL2-mediated AMPK signalling in autophagy. In the present study, autophagy function was characterized in hair cells (HCs) of Osbpl2-knockout mice and in Osbpl2-knockdown HEI-OC1 cells. The results showed that OSBPL2 deficiency impaired autophagy by inhibiting AMPK-TFEB signalling, resulting in aberrant accumulation of lipid droplets and apoptosis in auditory cells, which could be partially reversed by trehalose treatment. This study revealed the implications of OSBPL2 for autophagy in auditory cell and contributed to elucidating the pathogenesis of OSBPL2 mutations in hearing loss.

Keywords:  Apoptosis; Auditory cells; Autophagy; OSBPL2 deficiency

DOI:  https://doi.org/10.1016/j.cellsig.2026.112619
Nat Commun. 2026 May 25.

The V-ATPase/ATG16L1 axis drives membrane remodeling during epithelial morphogenesis.

Gabriel Baonza, Tatiana Alfonso-Pérez, Carlos Quintana-Quintana, Gonzalo Herranz, Carmen Gordillo-Vázquez, Yara El Mazjoub, L M Escudero, David G Míguez, Elisa Martí, Nuria Martínez-Martín, Fernando Martín-Belmonte.

Epithelial tubulogenesis shapes organs by transforming unpolarized epithelial cords into hollow tubes with central lumens. Posterior neural tube formation during secondary neurulation requires tightly coordinated membrane remodeling for de novo lumen formation and resolution, yet the role of autophagy in this process remains unclear. Autophagy operates through canonical and noncanonical pathways. While canonical autophagy is primarily degradative, the V-ATPase/ATG16L1-dependent Conjugation of ATG8 to Single Membranes (CASM) regulates LC3 lipidation on endocytic compartments. Using human neural tube organoids, MDCK cysts, and epithelial tube micropatterns selectively deficient in canonical or noncanonical autophagy, we demonstrate that CASM is essential for epithelial lumen resolution. Mechanistically, the V-ATPase/ATG16L1 axis coordinates junctional remodeling, phosphoinositide transitions, and Rab-dependent endocytic and recycling pathways to ensure single-lumen formation. These findings identify noncanonical autophagy as a spatially restricted membrane-remodeling mechanism that governs epithelial morphogenesis and reveal distinct, hierarchically balanced contributions of autophagy pathways during development.

DOI: https://doi.org/10.1038/s41467-026-73471-9
Int J Biol Sci. 2026 ;22(10): 5475-5494

SQSTM1/p62 UFMylation Enhances Autophagic Clearance of Pathogenic Mutant Huntingtin.

Xiaohui Wang, Xiaowei Lv, Honglv Jiang, Wenyun Zhu, Lindong Cao, Liang Zhou, Fang Lin, Rong Deng, Li-Fang Hu, Jingjing Ma, Jia-Bin Li, Guoqiang Xu.

  Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulating autophagy. However, it is still elusive which protein is UFMylated and how this modification modulates autophagy. Here, our quantitative proteomics and biochemical experiments identify SQSTM1/p62 as a UFMylation substrate and discover its two major UFMylation sites, K420 and K435. Mutating them to Arg (p622KR) completely abolishes the effect of p62 on autophagic activity. Fusion of UFM1ΔC4 to p622KR (p622KR-UFM1ΔC4) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.

Keywords:  Huntington's disease; SQSTM1/p62; UFMylation; autophagic degradation; mutant huntingtin; quantitative proteomics

DOI:  https://doi.org/10.7150/ijbs.127110
J Biol Chem. 2026 May 23. pii: S0021-9258(26)02056-9. [Epub ahead of print] 113184

p53 regulates mitochondrial function and alpha-synuclein aggregation in Parkinson's disease.

Kaiying Hou, Jialin Chen, Yuxin Xie, Tingting Liu, Jiaying Li, Chong Meng, Dongxue Niu, Meiyan Xian, Jingwen Li, Chaoyang Zhu, Hong Li, Jianshe Wei.

  Parkinson's disease (PD) is the second most common neurodegenerative disease, in which mitochondrial dysfunction and abnormal aggregation of alpha-synuclein (α-syn) play key roles in the pathology of PD. As a classic tumor suppressor, p53 has also been found to be involved in the pathological process of PD in recent years. However, the specific mechanism by which p53 regulates mitochondrial function and abnormal aggregation of α-syn is still unclear. Here, we observed that the expression of α-syn and p53 was increased and mitochondria were impaired in the MPTP-induced PD mouse model, leading us to propose speculation on whether p53 affects mitochondrial impairment and abnormal α-syn aggregation in PD pathology. Next, cellular experiments revealed that the p53 inhibition by pifithrin-α regulates mitochondrial function through mitophagy and mitochondrial dynamics, then ameliorates oxidative stress and apoptosis in PD. Meanwhile, the in vitro study showed that the p53 protein interacted with α-syn to accelerate the process of α-syn liquid-liquid phase separation and amyloid fibril formation, promoting the development of PD pathology. In summary, p53 modulates mitochondrial function through mitophagy and mitochondrial dynamics, stimulating the pathogenic aggregation of α-syn protein and neurodegeneration in Parkinson's disease.

Keywords:  Parkinson's disease; alpha-synuclein; mitochondrial dynamics; mitophagy; p53

DOI:  https://doi.org/10.1016/j.jbc.2026.113184
bioRxiv. 2026 May 14. pii: 2026.05.12.724395. [Epub ahead of print]

Small-molecule modulators of HIPK4 activity and proteostasis.

Zaile Zhuang, Riley K Togashi, Patrick Kearney, Ian Pass, Steven M Swick, Fu-Yue Zeng, Andrey A Bobkov, Lynn M Fujimoto, Shubhankar Dutta, Athina Zerva, Nicolai D Raig, Debasmita Saha, Atoosa Emami, Martin P Schwalm, Bradley K Moon, Samuel T Howard, Stefan Knapp, Thomas Hanke, Thomas D Y Chung, James K Chen.

Homeodomain-interacting protein kinase 4 (HIPK4) is a dual-specificity kinase that is predominantly expressed in differentiating spermatids, required for sperm development, and a promising target for nonhormonal male contraception. Genetic and functional studies have established an essential role for HIPK4 in spermiogenesis, where it acts at least in part through regulation of the F-actin-scaffolded acroplaxome during spermatid head shaping. The direct molecular targets of HIPK4 and their downstream effectors remain poorly defined, and small-molecule probes would be versatile tools for further investigating HIPK4 functions. Synthetic HIPK4 ligands could also be valuable leads for the development of nonhormonal male contraceptives. Here, we report the discovery of a cyanoquinoline-based series of HIPK4 inhibitors with nanomolar potency. Our lead compounds are selective for HIPK4, both within the HIPK family and across the broader kinome, establishing this scaffold as a useful starting point for probe and lead development. Unexpectedly, we found that a subset of these cyanoquinolines also perturbs HIPK4 proteostasis in a cell type-specific manner. In spermatids, these compounds induce the formation of detergent-insoluble HIPK4 aggregates and promote interactions between this kinase and the autophagy receptor Tax1-binding protein 1 (TAX1BP1). Together, our findings establish cyanoquinoline ligands as a new chemotype for probing HIPK4 biology and advancing male contraceptive discovery.

DOI: https://doi.org/10.64898/2026.05.12.724395
Eur J Pharmacol. 2026 May 26. pii: S0014-2999(26)00513-3. [Epub ahead of print]1029 179031

Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.

Xiaoqing Ding, Rui Zhao, Wei Wu, Di Huang, Meng Wang, Yuting Wu, Peiqiang Zhou, Linxu Wang, Dan Zhao.

  Transient receptor potential melastatin 4 (TRPM4) channel plays an important role in regulation of endothelial dysfunction. However, whether TRPM4 contributes to the developing of atherogenesis remains unexplored. In this study, ApoE-/- mice feeding with a high-fat diet (HFD) for 16 weeks to establish atherosclerosis model, were administered with or without 9-phenanthrol (9-Phe), a specific inhibitor of TRPM4. Our data showed that TRPM4 expression levels in aortas, particularly on endothelium, were significantly increased in HFD-induced atherosclerotic mice. While pharmacological inhibition with 9-Phe failed to reduce the HFD-induced atherosclerotic plaque area, it significantly stabilized vulnerable plaques in HFD-fed ApoE-/- mice. Upon exposed to oxidized low-density lipoprotein (ox-LDL), TRPM4 expression level was notably upregulated in primary cultured endothelial cells (ECs). Both 9-Phe and knockdown of TRPM4 protected ox-LDL-induced impairment of cell viability. Furthermore, ox-LDL-treated ECs showed impaired migration ability and enhanced release of adhesion molecules, including ICAM-1, VCAM-1 and E-selectin, which was also alleviated by 9-Phe. Notably, 9-Phe also inhibited the ox-LDL-triggered autophagy and apoptosis in ECs. Mechanistically, ox-LDL upregulated TRPM4 expression and induced activation of AMPK and autophagy signaling pathway; AMPK agonist acadesine (AICAR) was able to abolish the protective effect of 9-Phe against excessive autophagy and apoptosis in ECs. Taken together, our study reveals that atherosclerotic stress-induced increase in TRPM4 expression may contribute to HFD-induced progression of atherosclerosis and 9-Phe prevents these pathological processes by blunting AMPK-Beclin1-mediated excessive autophagy and apoptosis in ECs. We suggest that TRPM4 may be a potential therapeutic target for preventing HFD-induced atherosclerosis.

Keywords:  9-Phenanthrol; Atherosclerosis; Endothelial injury; Ox-LDL; TRPM4

DOI:  https://doi.org/10.1016/j.ejphar.2026.179031
Toxicol Appl Pharmacol. 2026 May 26. pii: S0041-008X(26)00183-3. [Epub ahead of print] 117887

Carnosic acid alleviates cisplatin-induced acute kidney injury by enhancing prohibitin 2-dependent mitophagy.

Yan Chen, Chenming Xu, Yan Chen, Qiong Liu, Wu Yin.

  Cisplatin is an effective chemotherapeutic agent, but its clinical use is limited by nephrotoxicity characterized by renal tubular epithelial injury. In this study, we found that carnosic acid (CA), a natural phenolic diterpene derived from rosemary and sage, significantly alleviated cisplatin-induced renal dysfunction and tubular epithelial damage. Mechanistically, CA suppressed mitochondria-dependent apoptosis and reduced mitochondrial damage by activating mitophagy. Further analysis revealed that CA upregulated prohibitin 2 (PHB2), a key mitophagy receptor involved in mitochondrial quality control. Importantly, inhibition or silencing of PHB2 abolished CA-induced mitophagy and cytoprotective effects. These findings indicate that CA protects against cisplatin-induced acute kidney injury by maintaining mitochondrial homeostasis through PHB2-dependent mitophagy, suggesting its potential as a therapeutic strategy for preventing cisplatin-associated nephrotoxicity.

Keywords:  Acute Kidney Injury; Carnosic Acid; Mitochondrial Homeostasis; Mitophagy; PHB2

DOI:  https://doi.org/10.1016/j.taap.2026.117887
Science. 2026 May 28. 392(6801): eadu9554

Selective autophagy fine-tunes plant immunity to promote cell survival during viral infection.

Marion Clavel, Anita Bianchi, Roksolana Kobylinska, Roan Groh, Xi Zhang, Juncai Ma, Ranjith K Papareddy, Nenad Grujic, Lorenzo Picchianti, Ethan Stewart, Michael Schutzbier, Karel Stejskal, Juan Carlos de la Concepcion, Victor Sanchez de Medina Hernandez, Yoav Voichek, Pieter Clauw, Joanna Gunis, Gerhard Durnberger, Jens Christian Muelders, Annett Grimm, Arthur Sedivy, Mathieu Erhardt, Victoria Vyboishchikov, Peng Gao, Esther Lechner, Emilie Vantard, Thomas Potuschak, Jakub Jez, Elisabeth Roitinger, Pascal Genschik, Byung-Ho Kang, Yasin Dagdas.

RNA viruses co-opt host endomembranes to form replication complexes, often triggering cellular stress and immune responses. Here, we show that Arabidopsis thaliana activates selective autophagy to respond to viruses targeting mitochondria, chloroplasts, and the endoplasmic reticulum. Rather than degrading viral components, autophagy selectively removes the immune regulator Enhanced Disease Susceptibility 1 (EDS1) to prevent cell death. This targeted mechanism is mediated by oligomeric metabolic enzymes that moonlight as selective autophagy receptors, linking organelle stress to immune homeostasis. Our findings establish selective autophagy as an essential immune rheostat that fine-tunes defense responses and safeguards cellular integrity to promote host survival during viral infections.

DOI: https://doi.org/10.1126/science.adu9554