Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Unravelling metabolite-microbiome interactions in inflammatory bowel disease through AI and interaction-based modelling","authors":"Rebecca Hodgkiss ,&nbsp;Animesh Acharjee","doi":"10.1016/j.bbadis.2024.167618","DOIUrl":"10.1016/j.bbadis.2024.167618","url":null,"abstract":"<div><div>Inflammatory Bowel Diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract and colon affecting approximately 7 million individuals worldwide. The knowledge of specific pathology and aetiological mechanisms leading to IBD is limited, however a reduced immune system, antibiotic use and reserved diet may initiate symptoms. Dysbiosis of the gut microbiome, and consequently a varied composition of the metabolome, has been extensively linked to these risk factors and IBD. Metagenomic sequencing and liquid-chromatography mass spectrometry (LC-MS) of <em>N</em> = 220 fecal samples by <em>Fransoza</em> et al., provided abundance data on microbial genera and metabolites for use in this study. Identification of differentially abundant microbes and metabolites was performed using a Wilcoxon test, followed by feature selection of random forest (RF), gradient-boosting (XGBoost) and least absolute shrinkage operator (LASSO) models. The performance of these features was then validated using RF models on the Human Microbiome Project 2 (HMP2) dataset and a microbial community (MICOM) model was utilised to predict and interpret the interactions between key microbes and metabolites. The <em>Flavronifractor</em> genus and microbes of the families <em>Lachnospiraceae</em> and <em>Oscillospiraceae</em> were found differential by all models. Metabolic pathways commonly influenced by such microbes in IBD were CoA biosynthesis, bile acid metabolism and amino acid production and degradation.</div><div>This study highlights distinct interactive microbiome and metabolome profiles within IBD and the highly potential pathways causing disease pathology. It therefore paves way for future investigation into new therapeutic targets and non-invasive diagnostic tools for IBD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167618"},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815139","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}

{"title":"Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective","authors":"Chinmay Pal","doi":"10.1016/j.bbadis.2024.167617","DOIUrl":"10.1016/j.bbadis.2024.167617","url":null,"abstract":"<div><div>Alzheimer's disease (AD) poses a considerable worldwide health obstacle, marked by gradual cognitive deterioration and neuronal loss. While the molecular mechanisms underlying AD pathology have been elucidated to some extent, therapeutic options remain limited. Mitochondrial dysfunction has become recognized as a significant factor in the development of AD, with oxidative stress and disrupted energy metabolism being critical elements. This review explores the mechanistic aspects of small molecule targeting of mitochondria as a potential therapeutic approach for AD. The review explores the role of mitochondrial dysfunction in AD, including its involvement in the accumulation of β-amyloid plaques and neurofibrillary tangles, synaptic dysfunction, and neuronal death. Furthermore, the effects of oxidative stress on mitochondrial function were investigated, including the resulting damage to mitochondrial components. Mitochondrial-targeted therapies have attracted attention for their potential to restore mitochondrial function and reduce AD pathology. The review outlines the latest preclinical and clinical evidence supporting the effectiveness of small molecules in targeting mitochondrial dysfunction in AD. Additionally, it discusses the molecular pathways involved in mitochondrial dysfunction and examines how small molecules can intervene to address these abnormalities. By providing a comprehensive overview of the latest research in this field, this review aims to shed light on the therapeutic potential of small molecule targeting of mitochondria in AD and stimulate further research in this promising area of drug development.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167617"},"PeriodicalIF":4.2,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796465","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}

{"title":"SIRT5 mediated succinylation of SUCLA2 regulates TCA cycle dysfunction and mitochondrial damage in pancreatic acinar cells in acute pancreatitis","authors":"Wenbin Liu ,&nbsp;Xiaofeng Wang ,&nbsp;Dan Xu ,&nbsp;Fangchen Gong ,&nbsp;Lei Pei ,&nbsp;Song Yang ,&nbsp;Shanzhi Zhao ,&nbsp;Xiangtao Zheng ,&nbsp;Ranran Li ,&nbsp;Zhitao Yang ,&nbsp;Jian Fei ,&nbsp;Enqiang Mao ,&nbsp;Erzhen Chen ,&nbsp;Ying Chen","doi":"10.1016/j.bbadis.2024.167613","DOIUrl":"10.1016/j.bbadis.2024.167613","url":null,"abstract":"<div><div>Acute pancreatitis (AP) is a severe inflammatory disorder associated with metabolic reprogramming and mitochondrial dysfunction. This study investigated central carbon metabolism alterations in pancreatic acinar cells during AP, elucidated the molecular mechanisms of tricarboxylic acid (TCA) cycle disorders, and explored the role of protein hypersuccinylation in AP pathogenesis. Using in vitro and in vivo AP models, targeted metabolomics and bioinformatics analyses revealed TCA cycle dysregulation characterized by elevated succinyl-CoA and decreased succinate levels. Colorimetric assays, mass spectrometry, and site-directed mutagenesis demonstrated that SIRT5 downregulation led to SUCLA2 hypersuccinylation at K118, inhibiting succinyl-CoA synthetase activity and triggering a vicious cycle of succinyl-CoA accumulation and SUCLA2 succinylation. Adenovirus-mediated SIRT5 overexpression and SUCLA2 knockdown clarified the SIRT5-SUCLA2 pathway's role in regulating TCA cycle disorders. Protein succinylation levels positively correlated with pancreatic tissue damage and mitochondrial injury severity. Succinylome analysis identified cytochrome <em>c</em>1 (CYC1) as a key hypersuccinylated protein, and the SIRT5-SUCLA2 pathway regulated its succinylation level and electron transport chain complex III activity. Hypersuccinylation induced mitochondrial DNA release, activating the cGAS-STING pathway, contributing to multiple organ dysfunction syndrome. Modulating the SIRT5-SUCLA2 axis attenuated TCA cycle dysregulation, protein hypersuccinylation, mitochondrial damage, and inflammatory responses in AP. These findings reveal novel mechanisms linking the SIRT5-SUCLA2 axis, TCA cycle dysfunction, and protein hypersuccinylation in AP pathogenesis, providing potential therapeutic targets for AP treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167613"},"PeriodicalIF":4.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792979","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}

{"title":"tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes","authors":"Kim Kobar ,&nbsp;Lissandra Tuzi ,&nbsp;Jennifer A. Fiene ,&nbsp;Erin Burnley ,&nbsp;Kristianne J.C. Galpin ,&nbsp;Craig Midgen ,&nbsp;Brianne Laverty ,&nbsp;Vallijah Subasri ,&nbsp;Timmy T. Wen ,&nbsp;Martin Hirst ,&nbsp;Michelle Moksa ,&nbsp;Annaick Carles ,&nbsp;Qi Cao ,&nbsp;Adam Shlien ,&nbsp;David Malkin ,&nbsp;Sergey V. Prykhozhij ,&nbsp;Jason N. Berman","doi":"10.1016/j.bbadis.2024.167612","DOIUrl":"10.1016/j.bbadis.2024.167612","url":null,"abstract":"<div><div>Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline <em>TP53</em> mutations. We characterized the first LFS zebrafish hotspot mutants, <em>tp53</em> R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months. <em>tp53</em> R242H mutants had a higher lifetime tumor incidence compared to <em>tp53</em> null and R217H mutants, suggesting it is a more aggressive mutation. We observed mutation-specific tumor phenotypes across <em>tp53</em> mutants with associated diverse transcriptomic and DNA methylome profiles in <em>tp53</em> mutant larvae, impacting metabolism, cell signalling, and biomacromolecule synthesis and degradation. These <em>tp53</em> zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics that suggest metabolic rewiring and cellular signalling changes occur prior to tumor initiation, which will guide targeted therapeutics for LFS.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167612"},"PeriodicalIF":4.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792983","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}

{"title":"A dual sensing mechanism of eastern honeybee Apis cerana that upregulates the expression level of chemosensory protein CSP1 and enhances the binding affinity to loquat floral volatiles at low temperature","authors":"Jia-Qi Huang ,&nbsp;Li Zhang ,&nbsp;Fan Wu ,&nbsp;Jing Tan ,&nbsp;Ping Wen ,&nbsp;Wei Xu ,&nbsp;Hong-Liang Li","doi":"10.1016/j.bbadis.2024.167601","DOIUrl":"10.1016/j.bbadis.2024.167601","url":null,"abstract":"<div><div>As a native bee species, the eastern honeybee (<em>Apis cerana</em>) plays an essential role in pollinating loquat flowers, which bloom in early winter in China. This pollination behavior is closely related to <em>A. cerana</em>'s ability to adapt to low temperatures, which depends on the functionality of its chemoreceptive system. Transcriptome analysis revealed a significant upregulation of the <em>A. cerana</em> chemosensory protein 1 (CSP1) gene at low temperatures. Fluorescence competitive binding experiments indicated that nine chemical volatiles from loquat flowers exhibited a stronger binding affinity to CSP1 than to odorant binding protein 2 (OBP2). Thermodynamic analysis revealed that CSP1's binding affinity increases at low temperatures, with a static binding mechanism largely influenced by the specific volatile molecule rather than the type of olfactory soluble protein. Molecular docking and site-directed mutagenesis confirmed that F44 residue may play a key role in CSP1's binding to three primary volatile compounds. In summary, the present study identified a dual sensing mechanism in which low temperatures upregulated the expression of CSP1 and enhanced the binding affinity of CSP1 to loquat flower volatiles. These findings not only clarify <em>A. cerana</em>'s chemoreceptive mechanism toward loquat flower volatiles in pollination but also provide a theoretical basis for further exploring ecological adaptations between native bees and early-winter flowering plants.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167601"},"PeriodicalIF":4.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759329","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}

{"title":"Colchicine inhibits monosodium urate crystal-mediated inflammation by influencing F-actin formation","authors":"Lingjiang Zhu ,&nbsp;Yuqi Wang ,&nbsp;Lizhen Shan ,&nbsp;Yu Xue ,&nbsp;Georg Schett ,&nbsp;Martin Herrmann ,&nbsp;Lei Liu","doi":"10.1016/j.bbadis.2024.167602","DOIUrl":"10.1016/j.bbadis.2024.167602","url":null,"abstract":"<div><h3>Objectives</h3><div>To understand the mechanism by which colchicine inhibits the inflammatory properties of monosodium urate (MSU) crystal deposits and tophi.</div></div><div><h3>Methods</h3><div>We investigated the effects of colchicine on the inflammatory properties of monosodium urate (MSU) crystal deposits in several models: (i) <em>In vitro</em> tophus formation by MSU and neutrophils; (ii) MSU-induced peritonitis model; (iii) Alpha-1-antitrypsin-induced peritoneal MSU flare model; (iv) MSU-induced arthritis model. We measured neutrophil numbers, NET formation, IL-1β production and F-actin generation by MSU crystals. In addition, we tested the effect of actin inhibitors SMIFH2, Cytochalasin B and Latrunculin B in the models.</div></div><div><h3>Results</h3><div>Colchicine did not affect neutrophil numbers in all these models. However, colchicine was highly effective to inhibit NET formation, IL-1β production and F-actin generation indicating less pronounced tophus formation, lower inflammatory properties of tophi and reduced conversion from G-actin into F-actin, respectively. F-actin was shown to accumulate in tophi without presence of colchicine and being resistant to degradation by DNase I. Actin inhibitors SMIFH2 and Cytochalasin B significantly reduced IL-1β and neutrophil elastase levels and mitigated MSU-induced arthritis.</div></div><div><h3>Conclusion</h3><div>Colchicine effects on gout flares are not based on reducing neutrophil numbers but on changing the functional properties of tophi by reducing their DNase-resistant F-actin concentrations and thereby reducing the negative impact of NETs on IL-1β production and the pro-inflammatory state of tophi. Actin inhibitors may be interesting tools to convey anti-inflammatory properties and reduction of flares in gout patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167602"},"PeriodicalIF":4.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775544","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}

{"title":"Retinoic acid-induced alterations enhance eATP-mediated anti-cancer effects in glioma cells: Implications for P2X7 receptor variants as key players","authors":"Bartosz Szymczak ,&nbsp;Anna Pegoraro ,&nbsp;Elena De Marchi ,&nbsp;Marianna Grignolo ,&nbsp;Bartosz Maciejewski ,&nbsp;Joanna Czarnecka ,&nbsp;Elena Adinolfi ,&nbsp;Katarzyna Roszek","doi":"10.1016/j.bbadis.2024.167611","DOIUrl":"10.1016/j.bbadis.2024.167611","url":null,"abstract":"<div><div>Retinoic acid (RA) is a small, lipophilic molecule that inhibits cell proliferation and induces differentiation through activation of a family of nuclear receptors (RARs). The therapeutic potential of RA in the treatment of glioma was first evaluated two decades ago, but these attempts were considered not conclusive. Based on the complexity of tumor microenvironment and the role of purinergic signals within TME, we aimed to support RA-induced alterations in glioma cells with extracellular ATP.</div><div>Our experiments focused on defining the purinergic signaling dynamics of two different human glioma cell lines M059K and M059J subjected to RA-based differentiation protocol. The applied procedure caused considerable modulation in P2X7 receptor variants expression at the gene and protein level, and decrease in ecto-nucleotidase activity. Collectively, it led to the decrease in cell proliferation rate and migration, as well as boosted sensitivity to cytotoxic eATP influence. We confirmed that micromolar concentrations of ATP decreased cell viability by 40 and 20 % in RA-treated M059K and M059J cells, respectively. Moreover, the decrease in migration capability up to 60 % in the presence of 100 μM ATP was observed. Both effects were mediated by P2X7R activation and reversed in the presence of A740003 antagonist, confirming the role of P2X7 receptor.</div><div>We postulate that retinoic acid-induced changes coupled with micromolar eATP could be effective as anti-cancer treatment affecting the purinergic signaling. The obtained results point out the role of P2X7R variants in influencing potential of glioma cells, as well as the possibility of using these isoforms as therapeutic targets.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167611"},"PeriodicalIF":4.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775560","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}

{"title":"Nrf2 protects against oxidative damage induced by hemoglobin in the liver of grass carp (Ctenopharyngodon idella)","authors":"Ningjing Li ,&nbsp;Jialing Song ,&nbsp;Yan Yang ,&nbsp;Xiaoman Huang ,&nbsp;Ye Tian ,&nbsp;Bing Chen ,&nbsp;Li Lin ,&nbsp;Zhendong Qin","doi":"10.1016/j.bbadis.2024.167600","DOIUrl":"10.1016/j.bbadis.2024.167600","url":null,"abstract":"<div><div>Hemoglobin (Hb) releases during hemorrhaging and causes oxidative damage, further exacerbates the development of multiple diseases. Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that regulates cellular defenses against toxic and oxidative challenges. However, the regulation mechanism of Nrf2 in Hb-induced oxidative stress remains unclear in teleost. To accomplish this goal, a hemolysis model was established by injecting grass carp with phenylalanine (PHZ), and the immunofluorescence analysis (IFA) and hematoxylin and eosin (H&amp;E) staining revealed that PHZ-induced hemolysis caused Hb accumulation and hepatic vacuolization, resulted in tissue damage. Prussian blue, Sirius red, and Masson staining results revealed significant iron deposition and extensive collagen fiber accumulation in the liver. IFA and immunohistochemical analyses demonstrated that PHZ-induced hemolysis markedly increased the production of reactive oxygen species (ROS), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). The quantitative real-time PCR (qRT-PCR) analysis data revealed that the PHZ-induced hemolysis also significantly upregulated the expression of antioxidant-related genes through activation of the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/Nrf2 signaling pathway. To further explore the molecule regulation mechanism of PHZ-induced hemolysis, the RNA-seq analysis was performed, and the data revealed that the AMPK/Nrf2 and multiple programmed cell death pathways, including ferroptosis, autophagy, apoptosis, and necroptosis in PHZ injection groups were significant upregulated. In vitro, the hemin supplementation activated the expression of target genes in the AMPK/Nrf2 pathway detected by qRT-PCR. To further verify the regulation function of Nrf2, an Nrf2 activator (4OI) was supplemented, and the flow cytometer analysis results suggested that the Hb-induced cell damage was significantly attenuated. However, the supplementary of ML385 down-regulated the AMPK/Nrf2 pathway and aggravated the hemin induced cell death. In conclusion, these findings highlight the critical regulatory role of the AMPK/Nrf2 signaling pathway in protecting against Hb-induced oxidative damage in the liver of grass carp.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167600"},"PeriodicalIF":4.2,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775554","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}

{"title":"Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes","authors":"Milica Popovic ,&nbsp;Lea Isermann ,&nbsp;Simon Geißen ,&nbsp;Katharina Senft ,&nbsp;Theodoros Georgomanolis ,&nbsp;Stephan Baldus ,&nbsp;Christian Frezza ,&nbsp;Aleksandra Trifunovic","doi":"10.1016/j.bbadis.2024.167567","DOIUrl":"10.1016/j.bbadis.2024.167567","url":null,"abstract":"<div><div>It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome <em>c</em> oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment. Heart-specific COX10 depletion caused severe dilated cardiomyopathy, while skeletal muscle experiences less damage. Cardiac CIV deficiency triggered extensive metabolic remodelling and stress response activation, potentially worsening cardiomyopathy, whereas skeletal muscle showed no stress response or significant metabolic changes. Our findings highlight distinct tissue capacities for managing CIV deficiency, explaining how identical primary defects can lead to different phenotypic outcomes and contribute to the heterogeneous progression of mitochondrial diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167567"},"PeriodicalIF":4.2,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756043","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}

{"title":"USP13 inhibition exacerbates mitochondrial dysfunction and acute kidney injury by acting on MCL-1","authors":"Qian Wang ,&nbsp;Shihan Cao ,&nbsp;Zhenzhen Sun ,&nbsp;Wenping Zhu ,&nbsp;Le Sun ,&nbsp;Yuanyuan Li ,&nbsp;Dan Luo ,&nbsp;Songming Huang ,&nbsp;Yue Zhang ,&nbsp;Weiwei Xia ,&nbsp;Aihua Zhang ,&nbsp;Zhanjun Jia","doi":"10.1016/j.bbadis.2024.167599","DOIUrl":"10.1016/j.bbadis.2024.167599","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a globally recognized public health issue that lacks satisfactory therapeutic strategies. Deubiquitinase ubiquitin-specific protease 13 (USP13) regulates various pathophysiological processes via the deubiquitination of multiple substrates. However, its role in AKI remains unclear. To illustrate the role and underlying mechanism of USP13 in AKI, we subjected <em>Usp13</em> knockdown mice, and mice treated with the USP13 inhibitor spautin-1, and mice with USP13 overexpression plasmids to cisplatin challenge. Renal tubular epithelial cell injury and mitochondrial disturbances were determined in vitro. Immunoprecipitation and deubiquitylation assays were performed to verify the interactions between USP13 and myeloid cell leukemia (MCL-1). We observed a significant decrease of USP13 expression in cisplatin-challenged AKI mice and renal tubular epithelial cells. Overexpression of USP13 alleviated kidney injury, whereas knockdown or inhibition of USP13 further exacerbated AKI. Mechanistically, USP13 downregulation resulted in increased degradation of MCL-1 which is a key regulator of cell survival and mitochondrial function, and the resultant MCL-1 reduction disrupted mitochondrial homeostasis and aggravated renal tubular epithelial cell injury and death, contributing to AKI progression. In conclusion, our findings demonstrated that inhibition of USP13 could exacerbate mitochondrial dysfunction and AKI through its effects on MCL-1, and USP13 may serve as a target for AKI prevention and treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 3","pages":"Article 167599"},"PeriodicalIF":4.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752398","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}