Autophagy最新文献

{"title":"Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.","authors":"Jin Ju Lim, Sujin Noh, Woojun Kang, Bom Hyun, Byung-Hoon Lee, Seogang Hyun","doi":"10.1080/15548627.2024.2389607","DOIUrl":"10.1080/15548627.2024.2389607","url":null,"abstract":"<p><p>Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in <i>Drosophila</i> and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging <i>Drosophila</i> flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by <i>foxo</i> mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.<b>Abbreviations</b>: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2752-2768"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903915","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":"SIGMAR1/Sigma-1 receptor: a key regulator in stabilizing and translating <i>LC3B</i> mRNA for autophagosome formation.","authors":"Yu-Jie Chen, Jeffrey Knupp, Emily Wang, Peter Arvan, Billy Tsai","doi":"10.1080/15548627.2024.2413313","DOIUrl":"10.1080/15548627.2024.2413313","url":null,"abstract":"<p><p>Macroautophagy/autophagy degrades and recycles cellular constituents via the lysosome to maintain cellular homeostasis. Our study identified the endoplasmic reticulum (ER)-resident SIGMAR1 (sigma non-opioid intracellular receptor 1) as a critical regulator of the biosynthesis of Atg8-family proteins that leads to the lipidation that is essential during autophagosome formation. We demonstrate that SIGMAR1 stabilizes <i>MAP1LC3B/LC3B</i> and <i>GABARAP</i> mRNAs, promoting their localized translation proximal to the ER for efficient lipidation. Using single-molecule fluorescence <i>in situ</i> hybridization/smFISH and co-immunoprecipitation, we found that SIGMAR1 directly binds to a conserved region in the 3' UTR of <i>LC3B</i> mRNA, facilitating its translation, efficient lipidation, and proper integration into the phagophore membrane. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux. Our model suggests that SIGMAR1-mediated localized translation of Atg8-family proteins at the ER promotes efficient autophagosome formation, in contrast to recruiting preexisting cytosolic Atg8-family proteins to the lipidation machinery. Elucidating the role of SIGMAR1 in autophagy may provide better therapeutic strategies to prevent or treat autophagy-dependent neurodegenerative diseases, particularly given the highly druggable nature of SIGMAR1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2843-2845"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378706","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":"Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) enhances anticancer immunosurveillance.","authors":"Léa Montégut, Isabelle Martins, Guido Kroemer","doi":"10.1080/15548627.2024.2411854","DOIUrl":"10.1080/15548627.2024.2411854","url":null,"abstract":"<p><p>The plasma concentration of the macroautophagy/autophagy inhibitor DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) increases with aging and body mass index (BMI). Both advanced age and obesity are among the most important risk factors for the development of cancer. We observed that patients with cancer predisposition syndromes due to mutations in <i>BRCA1</i>, <i>BRCA2</i> and <i>TP53</i> exhibit abnormally high plasma DBI/ACBP levels. Additionally, patients without known cancer predisposition syndromes also manifest higher DBI/ACBP levels before imminent cancer diagnosis (within 0-3 years) as compared to age and BMI-matched controls who remain cancer-free. Thus, supranormal plasma DBI/ACBP constitutes a risk factor for later cancer development. Mouse experimentation revealed that genetic or antibody-mediated DBI/ACBP inhibition can delay the development or progression of cancers. In the context of chemoimmunotherapy, DBI/ACBP neutralization enhances tumor infiltration by non-exhausted effector T cells but reduces infiltration by regulatory T cells. This resulted in better cancer control in models of breast cancer, non-small cell lung cancer and sarcoma. We conclude that DBI/ACBP constitutes an actionable autophagy checkpoint for improving cancer immunosurveillance. <b>Abbreviation</b>: BMI, body mass index; CTL, cytotoxic T lymphocyte; DBI, diazepam binding inhibitor, acyl-CoA binding protein; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer; PDCD1/PD-1, programmed cell death 1; scRNA-seq, single-cell RNA sequencing; T_reg, regulatory T cell.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2836-2838"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482858","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":"Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.","authors":"Juan Yi, He-Ling Wang, Guang Lu, Hailong Zhang, Lina Wang, Zhen-Yu Li, Liming Wang, Yihua Wu, Dajing Xia, Evandro F Fang, Han-Ming Shen","doi":"10.1080/15548627.2024.2383145","DOIUrl":"10.1080/15548627.2024.2383145","url":null,"abstract":"<p><p>Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) <i>C. elegans</i> model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.<b>Abbreviations:</b> AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A₁; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2655-2676"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763193","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":"Cleavage of SQSTM1/p62 by the Zika virus protease NS2B3 prevents autophagic degradation of viral NS3 and NS5 proteins.","authors":"Peng Zhou, Qingxiang Zhang, Yueshan Yang, Wanrong Wu, Dong Chen, Zhenhua Zheng, Anan Jongkaewwattana, Hui Jin, Hongbo Zhou, Rui Luo","doi":"10.1080/15548627.2024.2390810","DOIUrl":"10.1080/15548627.2024.2390810","url":null,"abstract":"<p><p>Macroautophagy/autophagy plays a crucial role in inhibiting viral replication and regulating the host's immune response. The autophagy receptor SQSTM1/p62 (sequestosome 1) restricts viral replication by directing specific viral proteins to phagophores for degradation. In this study, we investigate the reciprocal relationship between Zika virus (ZIKV) and selective autophagy mediated by SQSTM1/p62. We show that NS2B3 protease encoded by ZIKV cleaves human SQSTM1/p62 at arginine 265 (R265). This cleavage also occurs with endogenous SQSTM1 in ZIKV-infected cells. Furthermore, overexpression of SQSTM1 inhibits ZIKV replication in A549 cells, while its absence increases viral titer. We have also shown that SQSTM1 impedes ZIKV replication by interacting with NS3 and NS5 and directing them to autophagic degradation, and that NS2B3-mediated cleavage could potentially alter this antiviral function of SQSTM1. Taken together, our study highlights the role of SQSTM1-mediated selective autophagy in the host's antiviral defense against ZIKV and uncovers potential viral evasion strategies that exploit the host's autophagic machinery to ensure successful infection.<b>Abbreviation:</b> Cas9: CRISPR-associated protein 9; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DENV: dengue virus; GFP: green fluorescent protein; IFA: indirect immunofluorescence assay; KIR: KEAP1-interacting region; KO: knockout; LIR: MAP1LC3/LC3-interacting region; mAb: monoclonal antibody; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; pAb: polyclonal antibody; PB1: Phox/BEM1 domain; R265A, a SQSTM1 construct with the arginine (R) residue at position 265 replaced with glutamic acid (A); SQSTM1: sequestosome 1; SQSTM1-C, C-terminal fragment of SQSTM1; SQSTM1-N, N-terminal fragment of SQSTM1; SVV: Seneca Valley virus; TAX1BP1: Tax1 binding protein 1; TBD: TRAF6-binding domain; TCID₅₀: 50% tissue culture infective dose; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild type; ZIKV: Zika virus; ZZ: ZZ-type zinc finger domain.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2769-2784"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918323","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":"AKT2-mediated lysosomal dysfunction promotes secretory autophagy in retinal pigment epithelium (RPE) cells.","authors":"Sayan Ghosh, Stacey Hose, Debasish Sinha","doi":"10.1080/15548627.2024.2413305","DOIUrl":"10.1080/15548627.2024.2413305","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with the non-neovascular or atrophic form being the most common. Current treatment options are limited, emphasizing the urgent need for new therapeutic strategies. Our key finding is that increased levels of AKT2 in the RPE cells impair lysosomal function and trigger secretory autophagy; a non-canonical macroautophagy/autophagy pathway where cellular materials are released via the plasma membrane rather than being degraded by lysosomes. We showed that this process involves a protein complex, AKT2-SYTL1-TRIM16-SNAP23, releasing factors contributing to drusen biogenesis, a clinical hallmark of AMD development. Importantly, SIRT5 can inhibit this pathway, potentially offering a protective effect. Understanding mechanisms by which this non-canonical autophagy pathway promotes extracellular waste accumulation could provide new insights into drusen biogenesis. Future therapies for atrophic AMD could focus on regulating secretory autophagy or manipulating proteins involved in this process.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2841-2842"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482852","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":"Clustering lysosomes around the MTOC: a promising strategy for SNCA/alpha-synuclein breakdown leading to parkinson disease treatment.","authors":"Yukiko Sasazawa, Yuki Date, Nobutaka Hattori, Shinji Saiki","doi":"10.1080/15548627.2024.2413295","DOIUrl":"10.1080/15548627.2024.2413295","url":null,"abstract":"<p><p>Macroautophagy/autophagy maintains cellular homeostasis by degrading cytoplasmic components and its disruption is linked to Parkinson disease (PD), which is characterized by dopamine depletion and the accumulation of SNCA/α-synuclein aggregates in neurons. Therefore, activation of autophagy is considered a therapeutic strategy for PD; however, autophagy inducers have not yet been developed as therapeutic drugs because they are involved in a wide range of signaling pathways. Here, we focused on the lysosomal clustering around the microtubule-organizing center (MTOC) that can regulate the process of autophagosome-lysosome fusion, the final step of autophagy, and examined how lysosomal clustering affects protein degradation through autophagy. Our study identified six compounds from a high-content screen of 1,200 clinically approved drugs that induce both lysosomal clustering and autophagy. Notably, albendazole reduced SNCA aggregates in a PD model by lysosomal clustering and autophagy. These findings suggest that targeting lysosomal clustering could offer new therapeutic insights for PD.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2839-2840"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482854","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":"Enhancing neuronal reticulophagy: a strategy for combating aging and APP toxicity.","authors":"Wenqing Mou, Yixian Cui","doi":"10.1080/15548627.2024.2375086","DOIUrl":"10.1080/15548627.2024.2375086","url":null,"abstract":"<p><p>Reticulophagy, which directs the endoplasmic reticulum (ER) to the phagophore for sequestration within an autophagosome and subsequent lysosomal degradation via specific receptors, is essential for ER quality control and is implicated in various diseases. This study utilizes <i>Drosophila</i> to establish an <i>in vivo</i> model for reticulophagy. Starvation-induced reticulophagy is detected across multiple tissues in <i>Drosophila</i>. Whole-body upregulation or downregulation of the expression of reticulophagy receptors, <i>atl</i> and <i>Rtnl1</i>, negatively affects fly health. Notably, moderate upregulation of reticulophagy in neuronal tissues by overexpressing these receptors reduces age-related degeneration. In a <i>Drosophila</i> Alzheimer model expressing human APP (amyloid beta precursor protein), reticulophagy is compromised. Correcting reticulophagy by enhancing <i>atl</i> and <i>Rtnl1</i> expression in the neurons promotes APP degradation, significantly reducing neurodegenerative symptoms. However, overexpression of mutated <i>atl</i> and <i>Rtnl1</i>, which disrupts the interaction of the corresponding proteins with Atg8, does not alleviate these symptoms, emphasizing the importance of receptor functionality. These findings support modulating reticulophagy as a therapeutic strategy for aging and neurodegenerative diseases associated with ER protein accumulation.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2819-2820"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499844","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":"Role of AMBRA1 in mitophagy regulation: emerging evidence in aging-related diseases.","authors":"Martina Di Rienzo, Alessandra Romagnoli, Giulia Refolo, Tiziana Vescovo, Fabiola Ciccosanti, Candida Zuchegna, Francesca Lozzi, Luca Occhigrossi, Mauro Piacentini, Gian Maria Fimia","doi":"10.1080/15548627.2024.2389474","DOIUrl":"10.1080/15548627.2024.2389474","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Aging is a gradual and irreversible physiological process that significantly increases the risks of developing a variety of pathologies, including neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system diseases. Mitochondria are the energy-producing organelles, and their proper functioning is crucial for overall cellular health. Over time, mitochondrial function declines causing an increased release of harmful reactive oxygen species (ROS) and DNA, which leads to oxidative stress, inflammation and cellular damage, common features associated with various age-related pathologies. The impairment of mitophagy, the selective removal of damaged or dysfunctional mitochondria by autophagy, is relevant to the development and progression of age-related diseases. The molecular mechanisms that regulates mitophagy levels in aging remain largely uncharacterized. AMBRA1 is an intrinsically disordered scaffold protein with a unique property of regulating the activity of both proliferation and autophagy core machineries. While the role of AMBRA1 during embryonic development and neoplastic transformation has been extensively investigated, its functions in post-mitotic cells of adult tissues have been limited due to the embryonic lethality caused by AMBRA1 deficiency. Recently, a key role of AMBRA1 in selectively regulating mitophagy in post-mitotic cells has emerged. Here we summarize and discuss these results with the aim of providing a comprehensive view of the mitochondrial roles of AMBRA1, and how defective activity of AMBRA1 has been functionally linked to mitophagy alterations observed in age-related degenerative disorders, including muscular dystrophy/sarcopenia, Parkinson diseases, Alzheimer diseases and age-related macular degeneration.&lt;b&gt;Abbreviations:&lt;/b&gt; AD: Alzheimer disease; AMD: age-related macular degeneration; AMBRA1: autophagy and beclin 1 regulator 1; APOE4: apolipoprotein E4; ATAD3A: ATPase family AAA domain containing 3A; ATG: autophagy related; BCL2: BCL2 apoptosis regulator; BH3: BCL2-homology-3; BNIP3L/NIX: BCL2 interacting protein 3 like; CDK: cyclin dependent kinase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CRL2: CUL2-RING ubiquitin ligase; DDB1: damage specific DNA binding protein 1; ER: endoplasmic reticulum; FOXO: forkhead box O; FUNDC1: FUN14 domain containing 1; GBA/β-glucocerebrosidase: glucosylceramidase beta; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IDR: intrinsically disordered region; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; MCL1: MCL1 apoptosis regulator, BCL2 family member; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MSA: multiple system atrophy; MYC: MYC proto-oncogene, bHLH transcription factor; NUMA1: nuclear mitotic apparatus protein 1; OMM; mitochondria outer membrane; PD: Parkinson disease; PHB2: prohibiti","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2602-2615"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903917","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":"Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.","authors":"Hao Liu, Jianming Xie, Cien Zhen, Lin Zeng, Hualin Fan, Haixia Zhuang, Du Feng","doi":"10.1080/15548627.2024.2395145","DOIUrl":"10.1080/15548627.2024.2395145","url":null,"abstract":"<p><p>Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term \"nucleoid-phagy\", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2821-2823"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121331","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}