Autophagy最新文献

{"title":"RABC1 regulates ER-phagy to maintain ER homeostasis in plants.","authors":"Shuai Hu, Xiaohui Ma, Zhengjia Wang, Jinbo Shen","doi":"10.1080/15548627.2026.2739788","DOIUrl":"10.1080/15548627.2026.2739788","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER)-phagy is an important ER quality-control pathway that selectively removes misfolded or unfolded proteins and damaged ER membranes through autophagic degradation in the vacuole. Recent studies have identified small guanosine triphosphatases (GTPases) as important regulators of the autophagy pathway. However, how they couple stress signals to ER-phagy remains poorly understood in plants. Our recent work demonstrated that RABC1 regulates ER-phagy under dithiothreitol (DTT)-, tunicamycin (TM)-, and heat-induced ER stress through interaction with the exocyst complex component SEC5A. Upon ER stress, green fluorescent protein (GFP)-RABC1 was recruited to the ATG8e-positive autophagosomes from the ER and Golgi in root cells, whereas autophagic flux and calnexin 1 (CNX1)-mRFP-tagged ER membranes turnover were impaired in the <i>rabc1</i> mutant. Together, our findings support a model in which RABC1 acts as a molecular switch that interacts with distinct effectors to regulate autophagy under different stress conditions.<b>Abbreviations:</b> RAB, ras-related in brain; ER, endoplasmic reticulum; GTPases, guanosine triphosphatases; GFP, green fluorescent protein; CNX1, calnexin 1; GDP, guanosine diphosphate; GTP, guanosine triphosphate; SAR1D, secretion associated ras related GTPase 1D; COPII, coat protein complex II; LDs, lipid droplets; DTT, dithiothreitol; TM, tunicamycin; TOR, target of rapamycin; ATG, autophagy-related; Rho, ras homology.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":14.3,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USF2 restricts enterovirus replication and transmission by inhibiting autophagy and vesicle-mediated viral spread.","authors":"Tianming Liang, Zeyu Peng, Ruizhi Xi, Shuang Chen, Guang Yin, Lin Wang, Tianying Wang, Guochao Wei","doi":"10.1080/15548627.2026.2677196","DOIUrl":"10.1080/15548627.2026.2677196","url":null,"abstract":"<p><p>Enteroviruses pose a substantial global health burden, and a complete understanding of host defense mechanisms is still evolving. Through proteomic profiling of coxsackievirus B3 (CVB3)-infected cells, we identified the host factor USF2 (upstream transcription factor 2) as significantly upregulated, a process that may be associated with the viral capsid protein VP4. Here, we characterize USF2 as a novel, infection-induced restriction factor. Functional studies demonstrate that USF2 knockdown enhances viral RNA replication without affecting entry, while its overexpression suppresses replication and cytopathic effects. Mechanistically, USF2 acts as a transcriptional repressor of autophagy-related genes, thereby inhibiting autophagosome formation. Crucially, USF2 depletion promotes the release of MAP1LC3/LC3-positive extracellular vesicles carrying infectious virus, defining its role in blocking a key route of vesicle-mediated viral dissemination. USF2 exhibits broad antiviral activity against multiple enteroviruses and other RNA viruses that depend on cytoplasmic membrane remodeling. Our findings reveal that the host deploys a virus-triggered transcriptional regulator to restrict enterovirus spread by suppressing macroautophagy/autophagy-dependent viral dissemination.<b>Abbreviations:</b> BafA1: bafilomycin A₁; CQ: chloroquine; CPE: cytopathic effect; CVB3: coxsackievirus B3; dpi: days post infection; DEGs: differentially expressed genes; EV-A71: enterovirus A71; EVs: extracellular vesicles; GFP: green fluorescent protein; LAMP1: lysosomal-associated membrane protein 1; TR: LysoTracker Red; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MOI: multiplicity of infection; TFEB: transcription factor EB; USF2: upstream transcription factor 2; UPR: unfolded protein response; VP1: viral capsid protein 1; VP4: viral capsid protein 4.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2846-2862"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.","authors":"Jingwei Shi, Yuzhe Wu, Xian Liu, Weijie Xia, Junnan Wu, Junsheng Lou, Xuzi Zhang, Jiacheng Zhang, Ningning Yang, Weiyi Chi, Linyi Xiang, Yuheng Zhang, Yun Shu, Ruize Miao, Jiayi Zhao, Xuwei Zhu, Jianjun Qi, Jian Xiao, Kailiang Zhou","doi":"10.1080/15548627.2026.2677180","DOIUrl":"10.1080/15548627.2026.2677180","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the &lt;i&gt;MT-RNR1/12S&lt;/i&gt; rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, &lt;i&gt;in vivo&lt;/i&gt; overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.&lt;b&gt;Abbreviations:&lt;/b&gt; AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion mole","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2695-2724"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MEN1/menin deficiency suppresses hepatocellular carcinogenesis via disrupting mitophagy-mediated mitochondrial homeostasis.","authors":"Chaochun Chen, Dafang Yu, Dekun Tang, Mengyuan Liu, Jiamei Zhu, Xuyan Wang, Guixue Dan, Lan Chen, Shumei Tang, Qianting Tian, Houmei Wang, Fuxue Meng, Tuo Zhang, Bing Guo, Tengxiang Chen, Haiyang Li, Bangming Jin","doi":"10.1080/15548627.2026.2677182","DOIUrl":"10.1080/15548627.2026.2677182","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with complex pathogenesis intertwined with metabolic and mitochondrial dysfunction. MEN1/menin is a protein with context-dependent functions in liver diseases. While MEN1 has been linked to HCC progression and mitochondrial homeostasis, its precise regulatory mechanism in these processes remains incompletely understood. Here, we report that MEN1 localizes to the outer mitochondrial membrane (OMM) in HCC cells, which is mediated by its N-terminal mitochondrial targeting sequence and the TOMM20 translocase complex. In a genetically engineered DEN- and CCl&lt;sub&gt;4&lt;/sub&gt;-induced HCC mouse model, hepatocyte-specific &lt;i&gt;men1&lt;/i&gt; deficiency significantly suppressed tumorigenesis, a phenotype associated with impaired mitochondrial homeostasis. Mechanistically, &lt;i&gt;MEN1&lt;/i&gt; deficiency disrupted mitochondrial function by manifesting as promoted mitochondrial fission, impaired oxidative phosphorylation, reduced ATP levels, and elevated reactive oxygen species during energy stress. Critically, &lt;i&gt;MEN1&lt;/i&gt; loss inhibited mitophagy via downregulating the PINK1-PRKN/Parkin pathway, which impaired clearance of dysfunctional mitochondria and promotes their cytotoxic accumulation. Moreover, &lt;i&gt;MEN1&lt;/i&gt; expression was upregulated in human HCC tissues, correlated with poor clinical outcomes and was positively associated with autophagy signatures. Notably, pharmacological activation of mitophagy reversed the tumor-suppressive effects of &lt;i&gt;MEN1&lt;/i&gt; deficiency &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. These findings identified a noncanonical role of mitochondrial MEN1 in driving HCC progression via regulating mitophagy homeostasis, and highlight the &lt;i&gt;MEN1&lt;/i&gt;-mitophagy axis as a potential therapeutic target for HCC.&lt;b&gt;Abbreviations&lt;/b&gt;: &lt;i&gt;Alb-Cre&lt;/i&gt;: albumin promoter-driven recombinase Cre; Baf A1: bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; CCl&lt;sub&gt;4&lt;/sub&gt;: carbon tetrachloride; Co-IP: co-immunoprecipitation; CQ: chloroquine; DEN: diethylnitrosamine; DNM1L: dynamin 1 like; DQ-BSA: self-quenched BODIPY-conjugated bovine serum albumin; Gal: galactose; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; HCC: hepatocellular carcinoma; WT: wild type; HMKO: hepatocyte-specific &lt;i&gt;men1&lt;/i&gt; knockout; IF: immunofluorescence; IHC: immunohistochemistry; IMM: inner mitochondrial membrane; KEGG: Kyoto Encyclopedia of Genes and Genomes; MEFs: mouse embryonic fibroblasts; MEN1-FL: full-length MEN1; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MTS: mitochondrial targeting sequence; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: RNA extraction and quantitative polymerase chain reaction; RNA-seq: RNA-sequencing; ROS: reactive oxygen species; sh&lt;i&gt;MEN1&lt;/","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2744-2766"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148058734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.","authors":"Gayatri Mohanan, Kumkum Nag, Harsh Singh Senger, Parvathy J, Purusharth I Rajyaguru","doi":"10.1080/15548627.2026.2694657","DOIUrl":"10.1080/15548627.2026.2694657","url":null,"abstract":"<p><p>The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes <i>ATG1</i>, <i>ATG2</i>, and <i>ATG9</i>. Consistent with these translational changes, <i>sbp1∆</i> cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.<b>Abbreviations</b>: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2929-2946"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feedback loops between DNMT1 and autophagy as well as senescence promotes organ aging and canities.","authors":"Lu Li, Xinyue Mao, Linda Xiaoyan Li, Huaping Xiao, Zhenkun Lou, Hongbo Liu, Julie Xia Zhou, Li Yao, Xiaogang Li","doi":"10.1080/15548627.2026.2677185","DOIUrl":"10.1080/15548627.2026.2677185","url":null,"abstract":"<p><p>Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in the mammalian genome, is reported to be decreased in an age-dependent manner, the decrease of <i>Dnmt1</i> mRNA does not result in a decrease of its protein. Instead, DNMT1 protein is increased in aged mouse tissues, which is responsible for the methylation of genes related to macroautophagy/autophagy, senescence repression, and melanin synthesis and transport in aged organs, resulting in a decline of autophagy, an increase of senescence in those organs, and a decrease in melanin production in hair follicles (canities) in response to ionizing radiation (IR). Genetic deletion and inhibition of DNMT1 can reverse these processes. The interaction of DNMT1 with ATG7 through its CXXC domain is essential for its degradation, and treatment with senolytics also downregulates DNMT1 in aged organs, supporting two feedback loops between them.<b>Abbreviations</b>: 4-OHT, 4-hydroxytamoxifen; ChIP, chromatinimmunoprecipitation; D, dasatinib; D-gal, D-galactose; DCT/Trp-2, dopachrometautomerase; DMRs, differentially methylated regions; DNAm, DNA methylation; DNMTs,DNA methyltransferases; DSBs, double-stranded breaks; ETO, etoposide; GST, glutathione-S-transferase; HEK293T,human embryonic kidney 293T; HEM, human epidermal melanocytes; Hydr, hydralazine;IP, immunoprecipitation; IR,  ionizingradiation; KIF1A, kinesin family member 1A; M, methylated; MmIMCD3,mouse inner-medullary collecting duct 3; MITF, melanocyte inducingtranscription factor; MSP, methylation specific PCR; NCBI, national center for biotechnologyinformation; N-me, N-methyladenosine; PBMCs, peripheral blood mononuclear cells;Pro, proliferating; Q, quercetin; Rapa, rapamycin; RRBS, reduced representationbisulfite sequencing; RT, reverse transcription; SA-GLB1/β-Gal, senescence-associatedgalactosidase beta 1; SASP, senescence-associated secretory phenotype; Sen, senescent; SNP, single nucleotidepolymorphism; TYR, tyrosinase; TYRP1/Trp-1, tyrosinase related protein 1; UHRF1,ubiquitin like with PHD and ring finger domains 1; UM, unmethylated; UTR, untranslatedregion; WGBS, whole-genome bisulfite sequencing.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2809-2830"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"It's apples and oranges (or chalk and cheese, depending on where you live): RPM versus RCF.","authors":"Daniel J Klionsky","doi":"10.1080/15548627.2026.2685350","DOIUrl":"10.1080/15548627.2026.2685350","url":null,"abstract":"<p><p>At <i>Autophagy</i> we request that authors express centrifugal values as relative centrifugal force (RCF) or g-force as opposed to revolutions per minute (RPM). This is not an arbitrary decision but to understand the reason we need to provide a brief explanation of the difference between these two terms and, yes, there is a difference. Hence, it is annoying when during the editing process we request that an author convert a stated value such as \"12,000 RPM\" to \"×g\" and they simply return the paper with \"12,000 ×g.\" The problem is that \"12,000 RPM\" is not equivalent to \"12,000 ×g.\"</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":"22 10","pages":"2521"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RYR:ATP6V0A1 complexes couple ER-lysosome contact sites to dynamic autophagy control.","authors":"Jens Loncke, Manon Callens, Geert Bultynck, Tim Vervliet","doi":"10.1080/15548627.2026.2669981","DOIUrl":"10.1080/15548627.2026.2669981","url":null,"abstract":"<p><p>Ryanodine receptors (RYRs) are ER-resident Ca²⁺-release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER-lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca²⁺ release. In human iPSC-derived cortical neurons, spontaneous RYR activity promotes lysosomal secretion, depleting the intracellular lysosomal pool and inhibiting autophagic flux. RYR inhibition promotes ERlysosome contacts, limits lysosomal secretion, and restores lysosome availability for autophagosome fusion and cargo degradation (including APP). Conversely, disrupting the RYR:ATP6V0A1 interaction using a RYR-derived protein fragment serving as a \"decoy\" for ATP6V0A1 evokes RYR hyperactivity and stimulates lysosomal secretion. In this Punctum, we discuss how this RYR2:ATP6V0A1 \"contact-site hub\" may be perturbed in disease and highlight open questions on how lysosomes decode RYR-derived Ca²⁺ signals.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2977-2979"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical stress-mediated ferritinophagy aggravates cartilage endplate degeneration via a PIEZO1-NCOA4-ZBP1 axis.","authors":"Wenchao Wang, Dingfei Qian, Shengyao Sun, Yawei Yao, Xiaoqing Yang, Weibo Liu, Zelong Song, Haichao Yu, Linhao Hou, Peihong Hou, Jiayan Wu, Zhihao Ma, Jinlong Ma, Fanqi Hu, Hua Wang, Xuesong Zhang","doi":"10.1080/15548627.2026.2677183","DOIUrl":"10.1080/15548627.2026.2677183","url":null,"abstract":"<p><p>Abnormal mechanical stress is closely linked to intervertebral disc degeneration (IVDD). Iron homeostasis disorder occurs in various degenerative diseases, including IVDD. PIEZO1 serves as a mechanosensitive cation channel, involving in multiple physiological and pathological processes; however, its potential association with iron homeostasis and IVDD remain to be elucidated. Here, it is discovered that PIEZO1 accumulates in cartilage endplate (CEP) during IVDD, accompanied by intensive ferritinophagy. Specific activation of PIEZO1 or NCOA4 (nuclear receptor coactivator 4) aggravates CEP degeneration. Conversely, chondrocyte-specific knockout of <i>Piezo1</i> mitigates CEP degeneration by restoring the labile iron pool and stabilizing the mitochondrial genome. Mechanistically, PIEZO1-mediated nuclear translocation of YAP1 (Yes1 associated transcriptional regulator) enhances NCOA4-dependent ferritinophagy by promoting extracellular Ca²⁺ influx under oxidative stress. Moreover, ferritinophagy induces in the accumulation and release of Z-form mitochondrial DNA (Z-mtDNA), resulting in the activation of ZBP1 (Z-DNA binding protein 1), ultimately leading to NFKB-dependent inflammatory cascade. Therapeutically, blocking PIEZO1-mediated calcium influx or suppressing YAP1 activation alleviates ferritinophagy. Additionally, <i>Ncoa4</i> silencing attenuates Z-mtDNA-ZBP1-NFKB axis-driven IVDD. Collectively, our findings suggest that mechanical overload induces ferritinophagy-dependent CEP degeneration via PIEZO1 activation and subsequent upregulation of the Z-mtDNA-ZBP1-NFKB axis, which might furnish a therapeutic target for IVDD.<b>Abbreviation</b>: AAV: adeno-associated virus; ALP: alkaline phosphatase; ARS: alizarin red S; BV:TV: bone volume:total volume; CAMK2/CaMKII: calcium/calmodulin dependent protein kinase II; CEP: cartilage endplate; CEPCs: cartilage endplate chondrocytes; ChIP: chromatin immunoprecipitation; CKO: conditional knockout; CsA: cyclosporin A; Co-IP: co-immunoprecipitation; DHI: disc height index; ECM: extracellular matrix; EtBr: ethidium bromide; HIF: hypoxia inducible factor; IVDD: intervertebral disc degeneration; KD: knockdown; LAT: large tumor suppressor kinase; LSI: lumbar spine instability; MDA: malondialdehyde; Mito-ROS: mitochondrial reactive oxygen species; MRI: magnetic resonance imaging; mtDNA: mitochondrial DNA; NCOA4: nuclear receptor coactivator 4; PCBP: poly(rC) binding protein; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription; SOFG: safranin O and fast green; WWTR1/TAZ: WW domain containing transcription regulator 1; TEAD1: TEA domain transcription factor 1; TEM: transmission electron microscopy; YAP1: Yes1 associated transcriptional regulator; ZBP1: Z-DNA binding protein 1; Z-DNA: Z-form DNA; Z-mtDNA: Z-form mitochondrial DNA.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2767-2788"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMN/NAD⁺ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.","authors":"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","doi":"10.1080/15548627.2026.2677181","DOIUrl":"10.1080/15548627.2026.2677181","url":null,"abstract":"<p><p>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.<b>Abbreviations</b>: 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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2725-2743"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}