Autophagy [JOURNAL]
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200 papers
Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
Qu Y, Ren S, Liao Y … +5 more , Qiu X, Tan L, Song C, Sun Y, Ding C
Autophagy · 2026 May · PMID 41612592 · Full text
Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved mul...
Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy. CCCP: carbonyl cyanide m-chlorophenylhydrazone; COX4/COX IV: cytochrome c oxidase subunit 4; CQ: chloroquine; DENV: dengue virus; DNM1L/DRP1: dynamin 1 lik;ETC: electron transport chain; FIS1: fission, mitochondrial 1; HBV: hepatitis B virus; IAV: influenza A virus; IMM: inner mitochondrial membrane; JEV: japanese encephalitis virus; MAVS: mitochondrial antiviral signaling protein; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MFN2: mitofusin 2; MOI: multiplicity of infection; MV: measles virus; NDV: Newcastle disease virus; OMM: outer mitochondrial membrane; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; RLR: RIG-I-like receptor; SDHA: succinate dehydrogenase complex flavoprotein subunit A; TCA: tricarboxylic acid cycle; TCID: tissue culture infective doses; TEM: transmission electron microscopy; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20.
Deubiquitinase USP15 restricts LC3-dependent targeting of .
Rahlwes KC, Campos PC, Dias BRS … +2 more , Párraga Solórzano PK, Shiloh MU
Autophagy · 2026 May · PMID 41606832 · Full text
Macroautophagy/autophagy enables macrophages to degrade intracellular (Mtb), and this defense depends on E3 ubiquitin ligases such as PRKN/PARKIN/PARK2 and SMURF1, which tag Mtb-associated structures for lysosomal clear...
Macroautophagy/autophagy enables macrophages to degrade intracellular (Mtb), and this defense depends on E3 ubiquitin ligases such as PRKN/PARKIN/PARK2 and SMURF1, which tag Mtb-associated structures for lysosomal clearance. Deubiquitinases (DUBs) counter ubiquitin ligases by removing ubiquitin from molecular targets. We hypothesized that DUBs might offset ubiquitin ligase activity and negatively regulate host immunity to Mtb. Here, we identify USP15 (ubiquitin specific peptidase 15) as a negative regulator of MAP1LC3/LC3-dependent targeting pathways (consistent with xenophagy or CASM/LAP-related ATG8ylation) that mediate macrophage immunity to Mtb. Using a targeted knockdown screen in mouse macrophages, we found that loss increased K63-linked ubiquitination and LC3 recruitment to Mtb-associated structures, leading to reduced bacterial replication. These effects required USP15's catalytic activity and were reversed by knockdown of PRKN or inhibition of autophagy initiation. In primary human macrophages, knockdown similarly enhanced LC3 targeting and restricted Mtb growth. Importantly, pharmacological inhibition of USP15 with a selective small molecule decreased Mtb burden in human macrophages. Our findings identify USP15 as a suppressor of macrophage immunity and suggest that targeting deubiquitinases may represent a promising host-directed therapeutic strategy against tuberculosis.: CFU: colony-forming unit; DUBs: deubiquitinases; K48-Ub: K48-linked ubiquitin; K63-Ub: K63-linked ubiquitin; Mtb-pLux: luminescent Mtb strain Mtb; ; MOI: multiplicity of infection; NTC: non-targeting control; TB: tuberculosis.
Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
Rahman FA, Graham MQ, Quadrilatero J
Autophagy · 2026 May · PMID 41603537 · Full text
Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such a...
Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.: AIFM1: apoptosis inducing factor mitochondria associated 1; ATG: autophagy related; ATG7: autophagy related 7; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; BCL2L13: BCL2 like 13; CSA: cross-sectional area; CYCS: cytochrome c, somatic; EDL: extensor digitorum longus; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAS: gastrocnemius; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MYH: myosin heavy chain; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase 1; PLANT: plantaris; PRKN: parkin RBR E3 ubiquitin protein ligase; QUAD: quadriceps; SLC25A4: solute carrier family 25 member 4; SOD2: superoxide dismutase 2; SOL: soleus; SQSTM1: sequestosome 1; TFAM: transcription factor A, mitochondrial; VDAC1: voltage dependent anion channel 1.
SNX16 functions as a nutrient-sensitive regulator of autophagosomal components recycling.
Que H, Rong Y
Autophagy · 2026 May · PMID 41593027 · Full text
In macroautophagy/autophagy, the inner membrane of the autophagosome and its contents are degraded within the autolysosome, while outer membrane proteins are recycled via a process known as autophagosomal components recy...
In macroautophagy/autophagy, the inner membrane of the autophagosome and its contents are degraded within the autolysosome, while outer membrane proteins are recycled via a process known as autophagosomal components recycling (ACR). ACR is mediated by the recycler complex, powered by dynein-dynactin complexes, and regulated by RAB32-family small GTPases. However, it remains unknown whether ACR is subject to nutrient signal regulation or whether additional molecular components participate in the recycler complex. Our latest research identifies SNX16 as a new component of the recycler complex and reveals that MTORC1 phosphorylates SNX16, enabling SNX16 to function as a nutrient sensor that regulates ACR.
Correction.
Autophagy · 2026 Jan · PMID 41579344 · Publisher ↗
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Acetyl-CoA as a metabolic switch for selective mitophagy.
Tang D, Kang R, Klionsky DJ
Autophagy · 2026 Feb · PMID 41574966 · Full text
A recent study published in by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic chec...
A recent study published in by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
Li J, Wang W, He L … +1 more , Zhou Q
Autophagy · 2026 Apr · PMID 41568773 · Full text
Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria...
Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.
Lactucopicrin promotes the autophagic degradation of MAP2K4/MKK4 by mediating CCDC50 palmitoylation to alleviate osteoarthritis progression.
Li W, Sun Q, Hu K … +13 more , Tang D, Yang C, Xie Y, Peng X, Deng Y, Lu J, Qi Y, Lin Y, Sun H, Tian Q, Xu C, Tian X, Jiang H
Autophagy · 2026 Mar · PMID 41566717 · Full text
Macroautophagy/autophagy plays a crucial role in maintaining cellular homeostasis and protecting against osteoarthritis (OA). Its dysregulation contributes to OA progression by promoting chondrocyte senescence, inflammat...
Macroautophagy/autophagy plays a crucial role in maintaining cellular homeostasis and protecting against osteoarthritis (OA). Its dysregulation contributes to OA progression by promoting chondrocyte senescence, inflammation, and cartilage degradation. Enhancing autophagic activity thus represents a promising therapeutic strategy for OA. In this study, we identified lactucopicrin (LCP) as an effective autophagy activator that alleviates OA progression in a mouse model induced by the destabilization of the medial meniscus, by reducing cartilage degeneration and preserving matrix integrity. Mechanistically, LCP enhances ZDHHC4-catalyzed palmitoylation of the cargo receptor CCDC50, facilitating the selective autophagic degradation of MAP2K4/MKK4, leading to the suppression of MAPK/JNK signaling and the attenuation of chondrocyte senescence. Structural analysis reveals that LCP directly binds to His72 of ZDHHC4 its p-hydroxybenzoic acid moiety, boosting enzymatic activity and promoting selective autophagy. These findings establish a novel ZDHHC4-CCDC50-MAP2K4/MKK4-MAPK/JNK regulatory axis linking palmitoylation, autophagy, and senescence, and identify LCP as a promising agent for targeting this pathway to inhibit OA progression. Furthermore, this study provides mechanistic insights into the crosstalk between autophagy, protein palmitoylation, and cellular senescence in degenerative joint disease.: ABE: acyl-biotin exchange; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5; CCDC50: coiled-coil domain containing 50; COL2A1: collagen, type II, alpha 1; COL10A1: collagen, type X, alpha 1; DARTS: drug affinity responsive target stability; DHHC: Asp-His-His-Cys catalytic motif; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HO hydrogen peroxide; LCP: lactucopicrin; IL6: interleukin 6; MAPK/JNK: mitogen-activated protein kinase; MAP2K4/MKK4: mitogen-activated protein kinase kinase 4; MMP13: matrix metallopeptidase 13; OA: osteoarthritis; p-MAPK/JNK: phosphorylated mitogen-activated protein kinase; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; ZDHHC: zinc finger, DHHC domain containing.
Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy.
Rivault A, Dussart-Gautheret J, Benhida R … +4 more , Martin AR, Auberger P, Jacquel A, Robert G
Autophagy · 2026 May · PMID 41566700 · Full text
The targeted degradation of oncogenic or misfolded proteins has emerged as a promising therapeutic strategy. While proteolysis-targeting chimeras (PROTACs) and related technologies have successfully hijacked the ubiquiti...
The targeted degradation of oncogenic or misfolded proteins has emerged as a promising therapeutic strategy. While proteolysis-targeting chimeras (PROTACs) and related technologies have successfully hijacked the ubiquitin-proteasome system to eliminate disease-driving proteins, recent advances highlight the lysosome as a powerful alternative degradation route. Lysosome-based degradation strategies offer broader substrate scope, subcellular targeting flexibility, and the ability to degrade proteins beyond the reach of the proteasome. In this review, we provide a comprehensive overview of synthetic molecules and engineered systems designed to traffic target proteins to the lysosome. These include lysosome targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagy-tethering compounds (ATTECs), and other modalities that exploit endogenous trafficking pathways for selective protein clearance. By mapping the current landscape of lysosome-targeting degraders, this article underscores the therapeutic potential of lysosomal proteolysis and outlines future directions for molecular engineering in this rapidly evolving field.
The PI4K2A-OSBPL6/ORP6-PS axis mediates lysosomal membrane repair to restore neuronal lipid homeostasis and promote neuronal survival after spinal cord injury.
Zhang H, Kang Y, Zhao T … +10 more , Huang D, Hu X, Di J, Zhang Y, Lu Y, Huang M, Li H, Yao S, Liu B, Rong L
Autophagy · 2026 May · PMID 41556583 · Full text
Dysfunction of the neuronal macroautophagy/autophagy-lysosome system is a critical contributor to neuronal death following spinal cord injury (SCI), but the underlying mechanisms remain elusive. Our study demonstrated th...
Dysfunction of the neuronal macroautophagy/autophagy-lysosome system is a critical contributor to neuronal death following spinal cord injury (SCI), but the underlying mechanisms remain elusive. Our study demonstrated that SCI induced impaired autophagic flux and lysosomal membrane permeabilization (LMP) in neurons. By combining bulk RNA sequencing with validation experiments, we observed the transient upregulation of the membrane repair factor PI4K2A, which was specifically enriched in lysosomes, after SCI. Crucially, ER-MS and IP-MS analyses revealed an interaction between PI4K2A and the endoplasmic reticulum lipid transfer protein OSBPL6/ORP6. This interaction led to the transport of phosphatidylserine (PS) to damaged lysosomal membranes, promoting LMP repair and subsequently reducing lipid droplet accumulation, which suppressed neuronal death. Furthermore, overexpression of neuronal PI4K2A , through an OSBPL6- and PS-dependent mechanism, reduced LMP-mediated lipid droplet accumulation and increased neuronal survival, thereby improving functional recovery after SCI. Collectively, our findings establish the PI4K2A-OSBPL6/ORP6-PS axis as a novel and essential mechanism for lysosomal membrane repair in neurons. This pathway is crucial for maintaining neuronal lipid homeostasis and represents a promising therapeutic target for reducing neuronal loss and improving functional recovery after central nervous system trauma.: AIF1/IBA1: allograft inflammatory factor 1; Baf A1: bafilomycin A; BMS: Basso Mouse Scale; CNS: central nervous system; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DS5: DS55980254; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HSPA5/GRP78: heat shock protein family A (HSP70) member 5; HT22: hippocampal neuronal cell line; KEGG: Kyoto Encyclopedia of Genes and Genomes; LD: lipid droplet; LC-MS: liquid chromatography-mass spectrometry; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LGALS3/GAL3: lectin, galactoside binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; LPC: lysophosphatidylcholine; LPE: lysophosphatidylethanolamine; MFGE8/lactadherin: milk fat globule EGF and factor V/VIII domain containing; MS: mass spectrometry; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); NEFH/NF200: neurofilament, heavy polypeptide; OSBPL6/ORP6: oxysterol binding protein-like 6; OSBPL8/ORP8: oxysterol binding protein-like 8; PC: phosphatidylcholine; PLA2G4A/cPLA2: phospholipase A2, group IVA (cytosolic, calcium dependent); PITT: phosphoinositide-initiated membrane tethering and lipid transport; PI4K2A: phosphatidylinositol 4-kinase type 2 alpha; PLS-DA: partial least squares discriminant analysis; PS: phosphatidylserine; PtdIns: phosphatidylinositol; PTDSS1: phosphatidylserine synthase 1; PUFAs: polyunsaturated fatty acids; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; ROS: reactive oxygen species; SCI: spinal cord injury; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TGs: triglycerides.
Apoptotic bodies derived from human umbilical cord mesenchymal stem cells improve recovery from myocardial infarction in swine.
Luo W, Li H, Zhang P … +7 more , Cao H, Dong Y, Gong Y, Zhu D, Xin Y, Liu Z, Gao L
Autophagy · 2026 Apr · PMID 41556578 · Full text
Apoptotic bodies (ABs) are a type of extracellular vesicles (EVs) that could contribute to the paracrine effect of stem cells. However, their potential in treating cardiovascular diseases is largely unexplored. This stud...
Apoptotic bodies (ABs) are a type of extracellular vesicles (EVs) that could contribute to the paracrine effect of stem cells. However, their potential in treating cardiovascular diseases is largely unexplored. This study investigated the therapeutic effects of ABs derived from human umbilical cord mesenchymal stem cells (MSCs) on cardiac recovery in a porcine model of myocardial infarction (MI). In vitro, ABs reduced apoptosis and cytotoxicity in cardiomyocytes under oxygen and glucose deprivation (OGD) conditions and enhanced the capacity of migration and tube formation in endothelial cells. In vivo, akin to MSCs, administration of ABs improved contractile function, reduced infarct size, and mitigated adverse remodeling in pig hearts with MI, concomitantly with increased cardiomyocyte survival and angiogenesis. These cardioprotective effects were mediated through the regulation of autophagy by activating the adenosine monophosphate - activated protein kinase (AMPK) and transcription factor EB (TFEB) signaling pathways. microRNAs contained in ABs were sequenced, revealing that let-7f-5p was the most abundant. let-7f-5p promoted AMPK phosphorylation by targeting protein phosphatase 2 regulatory subunit B alpha (PPP2R2A) and decreased TFEB phosphorylation by targeting MAP4K3 to regulate autophagy, thereby contributing to the effects of ABs. Overall, these findings indicate that MSC-derived ABs have the potential to be a promising and effective acellular therapeutic option for treating MI.
gene duplication in vertebrates: evolutionary divergence and its functional implications.
Zhang S, Koyama-Honda I, Hiratsuka D … +1 more , Mizushima N
Autophagy · 2026 Apr · PMID 41550068 · Full text
Macroautophagy (hereafter referred to as autophagy) requires the coordinated action of approximately 20 (autophagy related) genes. Duplication of genes has had a major impact on the evolution of the autophagy pathway a...
Macroautophagy (hereafter referred to as autophagy) requires the coordinated action of approximately 20 (autophagy related) genes. Duplication of genes has had a major impact on the evolution of the autophagy pathway among major lineages. One duplication hotspot is in vertebrates. However, the exact duplication timing, post-duplication evolutionary divergence patterns, and its relation to functional differences among paralogs have not been investigated in detail. Here, we demonstrate that most genes were likely duplicated by whole-genome duplication events near the root of vertebrates. We compared the sequence and gene expression divergence between paralogs and categorized the evolutionary fates (i.e., how ancestral function is divided between paralogs). Within the paralog pairs that evolved most asymmetrically, namely , ( and ), and , one paralog likely retained the ancestral function, allowing the other to evolve under less constraint. While no obvious asymmetry was observed between and in non-mammalian vertebrates, experienced marked sequence divergence and expression level reduction in mammals, suggesting a shift in balance. Expression patterns among the ( and ), ( and ), and ( and ) pairs were more consistent with hypofunctionalization/dosage sharing, such that ancestral function depends on both paralogs. We also demonstrate that both and can support autophagy, whereas only , but not , has autophagic function and discuss the relationship between autophagic function and evolutionary divergence. The present detailed analysis of gene duplication in vertebrates provides a critical timeline for interpreting functional differentiation between homologs.: ATG: autophagy related; BLAST: Basic Local Alignment Search Tool; DKO: double knockout; GFP: green fluorescent protein; GLMM: generalized linear mixed model; KO: knockout; LC3: MAP1LC3; MEF: mouse embryonic fibroblast; ns: non-significant; PAML: Phylogenetic Analysis by Maximum Likelihood; RPKM: reads per kilobase per million mapped reads; SVA: surrogate variable analysis; TMM: trimmed mean of M values; TMR: tetramethylrhodamine; WT: wild type.
Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability.
Paul S, Tomsick PL, Milner JP … +7 more , Biswas SR, Brindley S, DeFoor N, Zavar L, Wright G, Soto Y, Pickrell AM
Autophagy · 2026 Apr · PMID 41543010 · Full text
Micronuclei are formed during cell division when acentric fragments or lagging chromosomes cannot be incorporated into the primary nucleus. Macroautophagy/autophagy may reduce chromosomal instability (CIN) by clearing is...
Micronuclei are formed during cell division when acentric fragments or lagging chromosomes cannot be incorporated into the primary nucleus. Macroautophagy/autophagy may reduce chromosomal instability (CIN) by clearing isolated, atypical micronuclei. Other studies implicate that the loss of autophagy disrupts DNA repair pathways. However, whether aberrant mitosis contributing to CIN occurs when autophagy is inhibited has yet to be evaluated. We found impaired autophagy initiation contributes to CIN and facilitates the formation of micronuclei and other abnormal nuclear phenotypes either by genetic or pharmacological manipulation in multiple cell lines. We also found that loss of the integral autophagy protein ATG9A resulted in various types of mitotic errors that can contribute to the formation of micronuclei. ATG9A also localizes to centrosomes and midbody during cell division. Autophagy inhibition causes the overactivation and mislocalization of TBK1 (TANK binding kinase 1) into cytoplasmic, punctate structures that colocalize with SQSTM1/p62. This overactivation interferes with its function in cell division as a mitotic kinase and its role at the centrosome. These results indicate that loss of autophagy contributes to genomic instability from multiple angles, one of which being aberrant cell division.
Muscle meets Lysosomes: emerging strategies in muscular dystrophy.
Jaber A, Israeli D
Autophagy · 2026 Apr · PMID 41532585 · Full text
Duchenne muscular dystrophy (DMD) is caused by the loss of DMD (dystrophin), leading to sarcolemmal fragility and progressive muscle degeneration. Although adeno-associated viral (AAV) microdystrophin () therapies have a...
Duchenne muscular dystrophy (DMD) is caused by the loss of DMD (dystrophin), leading to sarcolemmal fragility and progressive muscle degeneration. Although adeno-associated viral (AAV) microdystrophin () therapies have advanced clinically, their benefits remain partial, highlighting the need to identify secondary cellular defects that limit therapeutic efficacy. In our recent study, we demonstrated that lysosomal dysfunction is a conserved, intrinsic, and persistent feature of DMD pathology. Using mouse, canine, and human dystrophic muscle, we show marked lysosomal membrane permeabilization (LMP), impaired acidification, defective proteolysis, and inefficient membrane repair, all hallmarks of compromised lysosomal integrity. Cholesterol accumulation within dystrophic myofibers further exacerbates these defects, linking lipid dysregulation to lysosomal injury and accelerated muscle degeneration. We find macroautophagy/autophagy impairment in DMD stems in part from reduced autophagosome-lysosome fusion, reframing autophagy failure as a downstream consequence of lysosomal damage. gene therapy only partially corrects these abnormalities and does not fully restore lysosomal stability. In contrast, combining with the lysosome-activating disaccharide trehalose produces synergistic benefits, improving muscle strength, architecture, and molecular signatures beyond either treatment alone. These findings position lysosomal dysfunction as a central driver of DMD pathophysiology and support therapeutic strategies that pair gene restoration with lysosomal enhancement.: AAV: adeno-associated virus; DAGC: DMD-associated glycoprotein complex; DMD: Duchenne muscular dystrophy; FDA: Food and Drug Administration; LMP: lysosome membrane permeabilization; MTOR: mechanistic target of rapamycin kinase; µDMD: microdystrophin.
Metabolites released from apoptotic cells in central nervous system orchestrates the pathological process of Alzheimer disease through improving autophagy.
Xiao F, Tan X, He A … +8 more , Zhou Y, Xu K, Yuan Z, Zhu Y, Liang C, Can D, Zhang J, Leng L
Autophagy · 2026 Apr · PMID 41518198 · Full text
Apoptosis, a programmed cell death process activated in Alzheimer disease (AD), is not limited to neurons but extends to all cell types within the central nervous system (CNS). However, how apoptotic cells mediate their...
Apoptosis, a programmed cell death process activated in Alzheimer disease (AD), is not limited to neurons but extends to all cell types within the central nervous system (CNS). However, how apoptotic cells mediate their impact on surrounding cells and contribute to the pathological progression of AD remains largely unclear. Here, we report that in 5×FAD mice, cells surrounding amyloid-β (Aβ) plaques undergo apoptosis, which occurs concurrently with elevated macroautophagy/autophagy. The autophagic flux, nevertheless, is impaired in AD, as evidenced by the simultaneous accumulation of MAP1LC3/LC3 and SQSTM1/p62. As a result, although there is an increased formation of autophagosomes, misfolded proteins fail to undergo proper degradation in the subsequent process. By profiling the "metabolomic secretome" of primary neurons and glial cells under different apoptotic stimuli, we identified spermidine as a conserved apoptotic metabolite messenger in the CNS. Spermidine is actively released from apoptotic neurons or glia cells and functions in a paracrine manner to induce autophagy activation in neighboring cells. Such an effect of enhancing autophagic flux promotes both the cargo encapsulation within autophagosomes and degradation in autolysosomes in nearby cells. Conversely, the blockade of spermidine release impairs autophagic flux, thereby exacerbating cognitive impairment and pathological progression in AD. These findings reveal a link between cell apoptosis and autophagy in AD, suggesting that spermidine supplementation could serve as a promising therapeutic strategy.: Aβ: β-amyloid; ACM: apoptotic conditioned medium; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; CNS: central nervous system; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; ELISA: enzyme linked immunosorbent assay; GFAP: glial fibrillary acidic protein; GSDMD: gasdermin D; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PANX1: pannexin 1; PBS: phosphate-buffered saline; SQSTM1/p62: sequestosome 1; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RT-PCR: reverse transcription quantitative real-time polymerase chain reaction; SMOX: spermidine oxidase; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; UV: ultraviolet; WT: wild-type.
Measuring lysosome damage and lysophagy in vivo.
Wu Z, Zhan H, Huang Z … +8 more , Wang C, Li B, Hu Y, Chen Z, Liu W, Gong W, Sang Y, Sun Q
Autophagy · 2026 Apr · PMID 41485143 · Full text
Lysosome homeostasis is vital for cellular fitness due to the essential roles of this organelle in various pathways. Given their extensive workload, lysosomes are prone to damage, which can stimulate lysosomal quality co...
Lysosome homeostasis is vital for cellular fitness due to the essential roles of this organelle in various pathways. Given their extensive workload, lysosomes are prone to damage, which can stimulate lysosomal quality control mechanisms such as biogenesis, repair, or autophagic removal - a process termed lysophagy. Despite recent advances highlighting lysophagy as a critical mechanism for lysosome maintenance, the extent of lysosome integrity perturbation and the magnitude of lysophagy in vivo remain largely unexplored. Additionally, the pathophysiological relevance of lysophagy is poorly understood. To address these gaps, it is necessary to develop quantifiable methods for evaluating lysosome damage and lysophagy flux in vivo. To this end, we created two transgenic mouse lines expressing a tandem fluorescent LGALS3/galectin 3 probe (tfGAL3), either constitutively or conditionally under Cre recombinase control, utilizing the property of LGALS3 to recognize damaged lysosomes. This tool enables spatiotemporal visualization of lysosome damage and lysophagy activity at single-cell resolution in vivo. Systemic analysis across various organs, tissues, and primary cultures from these lysophagy reporter mice revealed significant variations in basal lysophagy, both in vivo and in vitro. Additionally, this study identified substantial changes in lysosome integrity and lysophagy flux in different tissues under stress conditions such as starvation, acute kidney injury and diabetic modeling. In conclusion, these complementary lysophagy reporter models are valuable resources for both basic and translational research. AAV: adeno-associated virus; ATG7: autophagy related 7; CA-tfGAL3: cre-recombinase-activated tandem fluorescent LGALS3; DAPI: 4',6-diamidino-2-phenylindole; DM: diabetes mellitus; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HFD: high-fat diet; Igs2/H11/Hipp11: intergenic site 2; IST1: IST1 factor associated with ESCRT-III; KI: knock-in; LAMP1: lysosomal-associated membrane protein 1; LGALS3: lectin, galactoside-binding, soluble, 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; MEFs: mouse embryonic fibroblasts; NaOx: sodium oxalate; PDCD6IP: programmed cell death 6 interacting protein; PTECs: proximal tubular epithelial cells; RFP: red fluorescent protein; STZ: streptozotocin; TAM: tamoxifen; tfGAL3: tandem fluorescent LGALS3; TMEM192: transmembrane protein 192.
TBK1 orchestrates autophagy and endo-lysosomal pathways in human neurons.
Mordes DA, Smeyers J
Autophagy · 2026 Mar · PMID 41485128 · Full text
Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia (FTD), yet the mechanisms by which TBK1 loss leads to neurodegeneration remain unclear. Using deep proteomics and phospho-proteomics, we demonstr...
Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia (FTD), yet the mechanisms by which TBK1 loss leads to neurodegeneration remain unclear. Using deep proteomics and phospho-proteomics, we demonstrate that TBK1 regulates select macroautophagy/autophagy factors, targeting cargo receptors and autophagy initiation factors, and also sustains the phosphorylation of the late endosomal marker RAB7A in stem cells and stem cell-derived excitatory neurons. We further uncovered novel TBK1-dependent phosphorylation sites in the key autophagy protein SQSTM1/p62. Loss of TBK1 function results in a cell-autonomous neurodegenerative phenotype characterized by impaired neurite outgrowth and lysosomal dysfunction.
Senecavirus a VP2 protein orchestrates PRDX1 degradation through dual autophagy pathways: macroautophagy and chaperone-mediated autophagy.
Li Z, Yang X, Mao J … +8 more , Zeng P, Qi Y, Shi Y, Guo J, Zhou J, Wang D, Liu J, Hou L
Autophagy · 2026 Apr · PMID 41479169 · Full text
Co-adaptation between viruses and autophagy has equipped viruses with diverse strategies to regulate host redox homeostasis, thereby facilitating viral replication. However, the mechanisms by which viruses manipulate PRD...
Co-adaptation between viruses and autophagy has equipped viruses with diverse strategies to regulate host redox homeostasis, thereby facilitating viral replication. However, the mechanisms by which viruses manipulate PRDX1 (peroxiredoxin 1), a key antioxidative enzyme, via autophagy remain poorly understood. Here, we demonstrate that infection by Senecavirus A (SVA), an emerging picornavirus, induces PRDX1 degradation, and that PRDX1 negatively regulates viral replication. Decreased PRDX1 expression impairs cellular antioxidant defenses, leading to enhanced reactive oxygen species generation that facilitates SVA replication. Screening of viral proteins revealed that SVA VP1, VP2, and 3A induce PRDX1 degradation through vesicle formation-dependent macroautophagy. Notably, viral VP2 can also recruit HSPA8/HSC70 to specifically target PRDX1, directing it for degradation via LAMP2A-mediated chaperone-mediated autophagy (CMA). Collectively, these findings demonstrate that the SVA VP2 protein plays a central role in orchestrating both macroautophagy- and CMA-mediated PRDX1 degradation, establishing PRDX1 as a potential intervention target for countering SVA infection. AKT/protein kinase B: AKT serine/threonine kinase; ATP: adenosine triphosphate; BHK-21: baby hamster kidney-21; CAT: catalase; CCCP: BMDMs: bone marrow-derived macrophages; CMA: chaperone-mediated autophagy; co-IP: co-immunoprecipitation; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CQ: chloroquine; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DMSO: dimethyl sulfoxide; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSH: glutathione; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KO: knockout; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; mM: millimole; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetylcysteine; PI3K: phosphoinositide 3-kinase; PRDX1: peroxiredoxin 1; RT-qPCR: real-time quantitative reverse transcription polymerase chain reaction; ROS: reactive oxygen species; SD: standard deviation; SOD: superoxide dismutase; SQSTM1: sequestosome 1; SVA: Senecavirus A; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type; μg: microgram; μm: micrometer; μM: micromolar.
A novel mechanism of lysosome-dependent microautophagy of ER exit sites.
Bhattacharyya D, Klionsky DJ
Autophagy · 2026 Mar · PMID 41474136 · Full text
Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of a...
Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of adapting to stress, but the molecular details controlling their degradation under nutrient-stress conditions were largely unknown. A recent study by Liao et al. introduces a new mechanism in which ERES are degraded through lysosome-dependent microautophagy in response to nutrient stress. This process is uniquely facilitated by COPII components, the calcium-binding adaptor ALG2, and the ESCRT machinery. The authors demonstrate that inhibiting MTOR triggers calcium release from lysosomes, which then recruits ALG2, leading to SEC31 ubiquitination and subsequently promoting PDCD6IP/ALIX-ESCRT-dependent lysosomal engulfment of ERES. This research reveals an unexplored pathway for the quality control and recycling of secretory machinery, thereby improving our understanding of ER turnover and establishing a mechanistic link between nutrient sensing, autophagy, and remodeling of the secretory pathway.
PEX14 powers OPTN (optineurin) to drive peroxisome turnover.
Li H, Azevedo JE, Fransen M
Autophagy · 2026 Mar · PMID 41474135 · Full text
Cells maintain organelle integrity and metabolic balance through tightly coordinated quality control systems. Autophagy plays a central role by recycling damaged and unnecessary cellular components, with selective pathwa...
Cells maintain organelle integrity and metabolic balance through tightly coordinated quality control systems. Autophagy plays a central role by recycling damaged and unnecessary cellular components, with selective pathways providing specificity through dedicated receptors. Although OPTN is well-established as a receptor for mitophagy, aggrephagy, and xenophagy, its role in pexophagy, the selective autophagic degradation of peroxisomes, has only recently been recognized. Our recent work identifies the peroxisomal membrane protein PEX14 as a critical docking platform for OPTN, enabling recruitment of autophagic machinery and initiation of pexophagy. How PEX14 engages OPTN, what triggers this interaction, and how it drives the autophagic engulfment of peroxisomes remain unclear. In this punctum, we contextualize our findings and highlight unresolved questions that must be addressed to understand the physiological and pathological relevance of this process.
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