MitoSNO抑制α-酮戊二酸脱氢酶(KGDH)产生线粒体过氧化氢(mtH2O2)。

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Olivia Chalifoux,Samantha Sterman,Ben Faerman,Meijing Li,Stephanie Trezza,Marek Michalak,Luis B Agellon,Ryan J Mailloux
{"title":"MitoSNO抑制α-酮戊二酸脱氢酶(KGDH)产生线粒体过氧化氢(mtH2O2)。","authors":"Olivia Chalifoux,Samantha Sterman,Ben Faerman,Meijing Li,Stephanie Trezza,Marek Michalak,Luis B Agellon,Ryan J Mailloux","doi":"10.1016/j.jbc.2025.108510","DOIUrl":null,"url":null,"abstract":"Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"45 1","pages":"108510"},"PeriodicalIF":4.0000,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).\",\"authors\":\"Olivia Chalifoux,Samantha Sterman,Ben Faerman,Meijing Li,Stephanie Trezza,Marek Michalak,Luis B Agellon,Ryan J Mailloux\",\"doi\":\"10.1016/j.jbc.2025.108510\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).\",\"PeriodicalId\":15140,\"journal\":{\"name\":\"Journal of Biological Chemistry\",\"volume\":\"45 1\",\"pages\":\"108510\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-04-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biological Chemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jbc.2025.108510\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biological Chemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jbc.2025.108510","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

在这里,我们证明线粒体α-酮戊二酸脱氢酶(KGDH)产生的过氧化氢(mtH2O2)可以被MitoSNO抑制,从而减轻脂肪毒性。纳米摩尔范围内的MitoSNO在分离的肝脏线粒体中抑制mtH2O2约50%,而不破坏呼吸,而用于合成MitoSNO的线粒体选择性衍生物,线粒体选择性n -乙酰-青霉胺(MitoNAP),对mtH2O2的生成或氧化磷酸化(OxPhos)没有影响。此外,当给予低微摩尔浓度的MitoSNO时,离体肝脏线粒体中mtH2O2的产生几乎被消除。MitoSNO的有效抑制作用与2-酮-3-甲基戊酸(KMV)和丙戊酸(VA)相当,后者是kgdh介导mH2O2产生的选择性抑制剂。已知S1QEL 1.1 (S1)和S3QEL (S3)分别通过抑制复合体I和复合体III选择性抑制mtH2O2的发生,而不破坏呼吸,对肝脏线粒体产生mtH2O2的影响很小或没有影响。我们还发现它也是mtH2O2的主要来源,但MitoSNO和MitoNAP不影响这种与etc相连的酶产生mtH2O2。在棕榈酸盐(PA)和果糖(Fruc)诱导的脂肪中毒中,MitoSNO还抑制mtH2O2的产生,并部分恢复Huh-7细胞的线粒体呼吸。MitoSNO还可以防止细胞死亡,并消除这些Huh-7细胞的肝内脂质积累。MitoSNO消除了高脂饮食小鼠肝脏线粒体中mtH2O2的过度生成,并部分恢复了OxPhos。我们的研究结果表明,MitoSNO通过KGDH s -亚硝化干扰mtH2O2的产生,可能有助于缓解非酒精性脂肪性肝病(NAFLD)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).
Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信