Molecular and Cellular Biology最新文献

Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms. 功能缺失小鼠模型揭示了ULK1在骨髓增殖性肿瘤中的一种新的调节功能。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-07-23 DOI: 10.1080/10985549.2025.2529837

Diana Saleiro, Jeremy Q Wen, Markella Zannikou, Brian Lee, Ewa M Kosciuczuk, Sarah D Nehlsen, Adam Munshi, Xintong Chen, Chidera V Oku, Briana Hryhorysak, Jamie N Guillen Magaña, Jorge Heneche, Mariafausta Fischietti, Liliana Ilut, Sara H Small, Anitria Cotton, Trent Hall, Monique A Payton, Elspeth M Beauchamp, Feng Yue, Masha Kocherginsky, Elizabeth T Bartom, Ronald Hoffman, John D Crispino, Leonidas C Platanias

{"title":"Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.","authors":"Diana Saleiro, Jeremy Q Wen, Markella Zannikou, Brian Lee, Ewa M Kosciuczuk, Sarah D Nehlsen, Adam Munshi, Xintong Chen, Chidera V Oku, Briana Hryhorysak, Jamie N Guillen Magaña, Jorge Heneche, Mariafausta Fischietti, Liliana Ilut, Sara H Small, Anitria Cotton, Trent Hall, Monique A Payton, Elspeth M Beauchamp, Feng Yue, Masha Kocherginsky, Elizabeth T Bartom, Ronald Hoffman, John D Crispino, Leonidas C Platanias","doi":"10.1080/10985549.2025.2529837","DOIUrl":"https://doi.org/10.1080/10985549.2025.2529837","url":null,"abstract":"Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in Jak2V617F-mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-24"},"PeriodicalIF":3.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

miR-365-3p Regulates Gastrointestinal Dysfunction in Diabetes Mellitus Rats via the TLR4/MyD88/NF-κB Pathway. miR-365-3p通过TLR4/MyD88/NF-κB通路调控糖尿病大鼠胃肠道功能障碍

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-07-22 DOI: 10.1080/10985549.2025.2532581

Jiao Xiao, Bin Gao, Yan Xiao, Xiangjie Liu

{"title":"miR-365-3p Regulates Gastrointestinal Dysfunction in Diabetes Mellitus Rats via the TLR4/MyD88/NF-κB Pathway.","authors":"Jiao Xiao, Bin Gao, Yan Xiao, Xiangjie Liu","doi":"10.1080/10985549.2025.2532581","DOIUrl":"https://doi.org/10.1080/10985549.2025.2532581","url":null,"abstract":"Over half of diabetes mellitus (DM) patients suffer from gastrointestinal motility disorders. miR-365-3p is involved in DM progression, but its role in gastrointestinal motility disorders remains unclear. This study explored whether miR-365-3p affects gastrointestinal motility in diabetic rats via the TLR4/MyD88/NF-κB pathway. A DM rat model was established using a high-fat, high-sugar diet and injected with a miR-365-3p mimic/inhibitor. DM symptoms, gastric emptying, intestinal propulsion rates, and gastrointestinal transit time were assessed. HE and TUNEL staining evaluated gastrointestinal pathology and apoptosis. qRT-PCR detected miR-365-3p levels, while ELISA assessed gastrointestinal motility-related factors. Immunofluorescence and Western blot analyzed C-kit, TLR4, and pathway proteins. DM rats exhibited increased body weight, blood glucose, and glucose intolerance, with reduced fasting insulin, confirming successful modeling. miR-365-3p was downregulated in DM rats. Injection of miR-365-3p mimic alleviated DM symptoms, reduced gastrointestinal tissue damage and apoptosis, and improved motility. The TLR4 agonist CRX-527 impaired these effects. In conclusion, miR-365-3p overexpression alleviates DM symptoms, gastrointestinal injury, and motility disorders by inhibiting the TLR4/MyD88/NF-κB pathway, offering a potential therapeutic target.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-17"},"PeriodicalIF":3.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular Function of Midnolin and Its Relevance to Parkinson's Disease. Midnolin的分子功能及其与帕金森病的相关性。

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-07-22 DOI: 10.1080/10985549.2025.2535666

Yutaro Obara, Ayano Chiba

{"title":"Molecular Function of Midnolin and Its Relevance to Parkinson's Disease.","authors":"Yutaro Obara, Ayano Chiba","doi":"10.1080/10985549.2025.2535666","DOIUrl":"10.1080/10985549.2025.2535666","url":null,"abstract":"Midnolin (Midn) was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MIDN remained largely unknown for many years after its discovery, its molecular functions and relevance to diseases have gradually become clearer. In PC12 cells, a rat neuronal model cell line, liquidity factors that are necessary for neurite outgrowth are reported to induce Midn gene expression. In addition, MIDN is required for E3 ubiquitin-protein ligase parkin expression, suggesting that MIDN is important for the development and maintenance of neuronal functions. Notably, it was recently reported that MIDN plays fundamental roles in the ubiquitin-independent proteasomal degradation of various nuclear proteins and transcription factors. Regarding the relationship between MIDN and diseases, copy number loss of MIDN is associated with Parkinson's disease, suggesting that MIDN is a genetic risk factor for this disease. In addition, MIDN is relevant to many types of malignant cancer, including B-cell lymphoma and liver cancer. Thus, MIDN is an essential molecule for the maintenance of homeostasis, and its functional disorder triggers multiple diseases depending on the affected tissues/organs. MIDN therefore shows promise as a potential therapeutic target and prognostic biomarker.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-10"},"PeriodicalIF":2.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors. 泛素E3连接酶UBE3A调控与AMPA受体内吞循环相关的GRIPAP1和PACSIN1蛋白。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-07-16 DOI: 10.1080/10985549.2025.2470431

Laura Drebushenko, Natalya Belous, Fritz W Lischka, Qiong Zhou, Ayse Malci, Michael S Sidorov, Barrington Burnett, Martin L Doughty

{"title":"The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors.","authors":"Laura Drebushenko, Natalya Belous, Fritz W Lischka, Qiong Zhou, Ayse Malci, Michael S Sidorov, Barrington Burnett, Martin L Doughty","doi":"10.1080/10985549.2025.2470431","DOIUrl":"10.1080/10985549.2025.2470431","url":null,"abstract":"Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). Using a dual SMAD inhibition protocol to derive cortical neurons from human induced pluripotent stem cells, we examined UBE3A deletion effects on the neuronal proteome by liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS identified 645 proteins differentially abundant between UBE3A knockout (KO) and isogenic UBE3A wild-type control cortical neurons. Proteins with increased abundance with UBE3A loss of function include GRIPAP1 and PACSIN1, synaptic proteins implicated in AMPA receptor recycling. We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-16"},"PeriodicalIF":3.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MARBP-lncRNA Complexes Alter Gene Function Through Modulation of Epigenetic Landscape. MARBP-lncRNA复合物通过调控表观遗传景观改变基因功能。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-07-03 DOI: 10.1080/10985549.2025.2519156

Nilanjana Maji, Anindya Dutta, Animesh Anand, Subhrangsu Chatterjee, Samit Chattopadhyay

{"title":"MARBP-lncRNA Complexes Alter Gene Function Through Modulation of Epigenetic Landscape.","authors":"Nilanjana Maji, Anindya Dutta, Animesh Anand, Subhrangsu Chatterjee, Samit Chattopadhyay","doi":"10.1080/10985549.2025.2519156","DOIUrl":"https://doi.org/10.1080/10985549.2025.2519156","url":null,"abstract":"Chromatin structure in eukaryotes is organized into functional domains through protein-DNA complexes. The cis-acting DNA elements are attached to the nuclear matrix, known as scaffold/matrix attachment regions (S/MARs). The associated protein partners known as matrix-associated region binding proteins (MARBPs). The coordinated interactions between MARBP and MARs to the nuclear scaffold act as an anchor for chromatin attachment and influences the regulation of gene expression. MARBPs modulate local epigenetic landscape of chromatin through the epigenetic modifiers. This function is executed by participating in the posttranslational modifications (PTMs) of DNA and histones. Such epigenetic changes are governed by crosstalk between long noncoding RNAs (lncRNAs) and associated MARBPs. Thus, dysregulation of either MARBPs or lncRNAs may alter gene expression potentially contributing to various disease manifestations. In this review, we elaborate on regulatory crosstalk between lncRNAs and MARBPs, its implication in human diseases, and possible therapeutics.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-16"},"PeriodicalIF":3.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development. 缺氧信号在哺乳动物发育过程中对促红细胞生成素产生的细胞类型特异性调节。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-06-27 DOI: 10.1080/10985549.2025.2522720

Norio Suzuki, Taku Nakai, Yuma Iwamura, Koichiro Kato

{"title":"Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development.","authors":"Norio Suzuki, Taku Nakai, Yuma Iwamura, Koichiro Kato","doi":"10.1080/10985549.2025.2522720","DOIUrl":"https://doi.org/10.1080/10985549.2025.2522720","url":null,"abstract":"To maintain the oxygen supply to peripheral organs, the production of erythropoietin (EPO), an essential growth factor for red blood cells, is controlled in a hypoxia-inducible manner in mammals. The developmentally earliest site of EPO production, which is necessary for primitive erythropoiesis in the yolk sac and bloodstream, is found in a subset of neural crest and neuroepithelial cells during mid-stage embryonic development. These neural EPO-producing (NEP) cells maintain their immaturity and EPO-producing ability in their hypoxic microenvironment, which is inherent in developing embryos. After oxygenation of the fetus by the establishment of the circulatory system and EPO-driven erythropoiesis, the site of EPO production shifts to hepatocytes of the fetal liver, where erythropoiesis also occurs. In adult mammals, a specific fibroblastic cell fraction in the renal interstitium, known as renal EPO-producing (REP) cells, secretes the majority of EPO to support bone marrow erythropoiesis. Hypoxia-inducible transcription factors (HIFs) are involved in EPO production across NEP cells, hepatocytes, and REP cells, whereas the regulatory mechanisms are distinct for each cell type. This review summarizes the molecular mechanisms of EPO gene regulation throughout all life stages and discusses the associations of HIF signaling in EPO production with other stimuli, including inflammation and metabolism.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-9"},"PeriodicalIF":3.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus. ΔNp63β的差异转录活性是由一个同工型特异性c端编码的。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-06-23 DOI: 10.1080/10985549.2025.2514529

Abby A McCann, Morgan A Sammons

{"title":"Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus.","authors":"Abby A McCann, Morgan A Sammons","doi":"10.1080/10985549.2025.2514529","DOIUrl":"10.1080/10985549.2025.2514529","url":null,"abstract":"p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-17"},"PeriodicalIF":3.2,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expression of Concern: Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling. 关注表达：丝裂原刺激与端粒缩短共同激活DNA损伤反应和衰老信号。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-02-24 DOI: 10.1080/10985549.2025.2462481

引用次数: 0

Kinase Inhibitor-Induced Cell-Type Specific Vacuole Formation in the Absence of Canonical ATG5-Dependent Autophagy Initiation Pathway. 在缺乏典型atg5依赖性自噬起始途径的情况下，激酶抑制剂诱导细胞型特异性液泡形成。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-02-02 DOI: 10.1080/10985549.2025.2454421

Susan Jose, Himanshi Sharma, Janki Insan, Khushboo Sharma, Varun Arora, Sameera Puranapanda, Sonam Dhamija, Nabil Eid, Manoj B Menon

{"title":"Kinase Inhibitor-Induced Cell-Type Specific Vacuole Formation in the Absence of Canonical ATG5-Dependent Autophagy Initiation Pathway.","authors":"Susan Jose, Himanshi Sharma, Janki Insan, Khushboo Sharma, Varun Arora, Sameera Puranapanda, Sonam Dhamija, Nabil Eid, Manoj B Menon","doi":"10.1080/10985549.2025.2454421","DOIUrl":"10.1080/10985549.2025.2454421","url":null,"abstract":"Pyridinyl-imidazole class p38 MAPKα/β (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce cell-type specific defective autophagy resulting in micron-scale vacuole formation, cell death, and tumor suppression. We had earlier shown that this is an off-target effect of SB202190. Here we provide evidence that this vacuole formation is independent of ATG5-mediated canonical autophagosome initiation. While SB202190 interferes with autophagic flux in many cell lines parallel to vacuolation, autophagy-deficient DU-145 cells and CRISPR/Cas9 gene-edited ATG5-knockout A549 cells also undergo vacuolation upon SB202190 treatment. Late-endosomal GTPase RAB7 colocalizes with these compartments and RAB7 GTP-binding is essential for SB202190-induced vacuolation. A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor sorafenib as inhibitors of vacuolation and sorafenib co-treatment enhanced cytotoxicity of SB202190. Moreover, VE-821, an ATR inhibitor was found to phenocopy the cell-type specific vacuolation response of SB202190. To identify the factors determining the cell-type specificity of vacuolation induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole-forming and non-vacuole-forming cancer cell lines and identified a gene expression signature that may define sensitivity of cells to these small-molecules. Further analyses using small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting anti-cancer phenotype.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"99-115"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SIRT3 Deficiency Promotes Lung Endothelial Pyroptosis Through Impairing Mitophagy to Activate NLRP3 Inflammasome During Sepsis-Induced Acute Lung Injury. 在脓毒症诱导的急性肺损伤过程中，SIRT3缺陷通过损害有丝分裂来激活NLRP3炎症体，从而促进肺内皮细胞脓毒症。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 10.1080/10985549.2024.2426282

Congmin Yan, Xin Lin, Jingting Guan, Wengang Ding, Ziyong Yue, Zhiqiang Tang, Xiangqi Meng, Bo Zhao, Zhiqiang Song, Dongmei Li, Tao Jiang

{"title":"SIRT3 Deficiency Promotes Lung Endothelial Pyroptosis Through Impairing Mitophagy to Activate NLRP3 Inflammasome During Sepsis-Induced Acute Lung Injury.","authors":"Congmin Yan, Xin Lin, Jingting Guan, Wengang Ding, Ziyong Yue, Zhiqiang Tang, Xiangqi Meng, Bo Zhao, Zhiqiang Song, Dongmei Li, Tao Jiang","doi":"10.1080/10985549.2024.2426282","DOIUrl":"10.1080/10985549.2024.2426282","url":null,"abstract":"Acute lung injury (ALI) is a major cause of death in bacterial sepsis due to endothelial inflammation and endothelial permeability defects. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of sepsis-induced ALI. Sirtuin 3 (SIRT3) is a histone protein deacetylase involved in preservation of mitochondrial function, which has been demonstrated in our previous study. Here, we investigated the effects of SIRT3 deficiency on impaired mitophagy to promote lung endothelial cells (ECs) pyroptosis during sepsis-induced ALI. We found that 3-TYP aggravated sepsis-induced ALI with increased lung ECs pyroptosis and enhanced NLRP3 activation. Mitochondrial reactive oxygen species (mtROS) and extracellular mitochondrial DNA (mtDNA) released from damaged mitochondria could be exacerbated in SIRT3 deficiency, which further elicit NLRP3 inflammasome activation in lung ECs during sepsis-induced ALI. Furthermore, Knockdown of SIRT3 contributed to impaired mitophagy via downregulating Parkin, which resulted in mitochondrial dysfunction. Moreover, pharmacological inhibition NLRP3 or restoration of SIRT3 attenuates sepsis-induced ALI and sepsis severity in vivo. Taken together, our results demonstrated SIRT3 deficiency facilitated mtROS production and cytosolic release of mtDNA by impaired Parkin-dependent mitophagy, promoting to lung ECs pyroptosis through the NLRP3 inflammasome activation, which providing potential therapeutic targets for sepsis-induced ALI.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-16"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0