Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease.
Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease.
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DOI：
10.1016/j.redox.2017.11.005
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Zhou Z
中科院分区：
文献类型：
--
作者：
Hao L;Sun Q;Zhong W;Zhang W;Sun X;Zhou Z
酒精在肝脏代谢产生剧毒的乙醛。线粒体中的乙醛脱氢酶 2 (ALDH2) 分解乙醛会消耗 NAD+ 并产生活性氧/氮，这是酒精性肝病 (ALD) 发病机制的基本机制。与非靶向抗氧化剂相比，靶向线粒体的亲脂性泛醌 (MitoQ) 已被证明可以更好地防止线粒体氧化损伤。本研究旨在探讨 MitoQ 是否可以保留线粒体 ALDH2 活性并加速乙醛清除，从而预防 ALD。雄性 C57BL/6 J 小鼠暴露于酒精 8 周，并在最后 4 周补充 MitoQ（5 mg/kg/d）。 MitoQ 改善了酒精引起的氧化/亚硝化应激和谷胱甘肽缺乏症。它还通过调节 ALDH2 半胱氨酸 S-亚硝基化、酪氨酸硝化和 4-羟基壬烯醇加合物的形成，逆转酒精降低的肝脏 ALDH 活性并加速乙醛清除。 MitoQ 改善了谷胱甘肽耗尽条件下 Hepa-1c1c7 细胞中一氧化氮 (NO) 供体介导的 ADLH2 S-亚硝基化和硝化。此外，酒精导致循环乙醛水平升高，同时肠道 ALDH 活性降低，肠道屏障受损。相应地，MitoQ 逆转了酒精增加的血浆内毒素水平和肝脏 Toll 样受体 4 (TLR4)-NF-κB 信号传导，并随后抑制了炎症细胞浸润。 MitoQ 还通过增强脂肪酸 β-氧化来逆转酒精诱导的肝脏脂质积累。 MitoQ 逆转了酒精诱导的 ER 应激和细胞凋亡信号。这项研究表明，通过保留 ALDH2 活性来加速乙醛清除，对 MitoQ 对酒精诱导的肠肝轴发病机制的有益作用至关重要。 ALDH2 的 PTM 参与酒精性肝病的发病机制。 MitoQ 治疗加速乙醛解毒。 MitoQ 改善了乙醛相关的紧密连接破坏。 MitoQ 逆转酒精性肝病中 TLR4 介导的炎症反应。 MitoQ 可以抵消酒精引起的内质网应激和细胞凋亡。
Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD+ and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD. Male C57BL/6 J mice were exposed to alcohol for 8 weeks with MitoQ supplementation (5 mg/kg/d) for the last 4 weeks. MitoQ ameliorated alcohol-induced oxidative/nitrosative stress and glutathione deficiency. It also reversed alcohol-reduced hepatic ALDH activity and accelerated acetaldehyde clearance through modulating ALDH2 cysteine S-nitrosylation, tyrosine nitration and 4-hydroxynonenol adducts formation. MitoQ ameliorated nitric oxide (NO) donor-mediated ADLH2 S-nitrosylation and nitration in Hepa-1c1c7 cells under glutathion depletion condition. In addition, alcohol-increased circulating acetaldehyde levels were accompanied by reduced intestinal ALDH activity and impaired intestinal barrier. In accordance, MitoQ reversed alcohol-increased plasma endotoxin levels and hepatic toll-like receptor 4 (TLR4)-NF-κB signaling along with subsequent inhibition of inflammatory cell infiltration. MitoQ also reversed alcohol-induced hepatic lipid accumulation through enhancing fatty acid β-oxidation. Alcohol-induced ER stress and apoptotic cell death signaling were reversed by MitoQ. This study demonstrated that speeding up acetaldehyde clearance by preserving ALDH2 activity critically mediates the beneficial effect of MitoQ on alcohol-induced pathogenesis at the gut-liver axis. PTMs of ALDH2 participated in the pathogenesis of alcoholic liver disease. MitoQ treatment accelerated acetaldehyde detoxification. MitoQ ameliorated acetaldehyde-related tight junction disruption. MitoQ reversed TLR4-mediated inflammatory response in alcoholic liver disease. MitoQ counteracts alcohol-induced ER stress and cell apoptosis.
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影响因子：
4.1
作者：
Doorn, JA;Hurley, TD;Petersen, DR
通讯作者：
Petersen, DR
影响因子：
7.4
作者：
Abdelmegeed, Mohamed A.;Jang, Sehwan;Banerjee, Atrayee;Hardwick, James P.;Song, Byoung-Joon
通讯作者：
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DOI：
10.1111/j.1530-0277.2000.tb00012.x
发表时间：
2000-04-01
影响因子：
3.2
作者：
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通讯作者：
Fukui, H
影响因子：
6.5
作者：
Clugston, Robin D.;Jiang, Hongfeng;Blaner, William S.
通讯作者：
Blaner, William S.
影响因子：
3.8
作者：
Dong D;Zhong W;Sun Q;Zhang W;Sun X;Zhou Z
通讯作者：
Zhou Z