S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver
S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver
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DOI：
10.1152/ajpgi.00044.2006
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发表时间：
2006-11-01
影响因子：
4.5
通讯作者：
Darley-Usmar, Victor
中科院分区：
文献类型：
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作者：
Bailey, Shannon M.;Robinson, Gloria;Darley-Usmar, Victor
饮酒后发生的一个早期事件是线粒体功能障碍，这在线粒体蛋白质组变化、呼吸缺陷和线粒体 DNA (mtDNA) 损伤中表现得很明显。 S-腺苷甲硫氨酸（SAM）已成为治疗酒精性肝病的潜在疗法，其机制似乎涉及减少氧化应激和促炎细胞因子的产生以及减轻脂肪变性。由于线粒体是活性氧/氮的来源和氧化损伤的目标，我们测试了酒精暴露期间 SAM 处理可保留细胞器功能的假设。从喂食对照和含有或不含有 SAM 的乙醇饮食 5 周的大鼠的肝脏中分离线粒体。酒精喂养会导致状态 3 呼吸和呼吸控制比显着下降，而 SAM 给药可防止这些酒精介导的缺陷并保持肝脏 SAM 水平。 SAM 治疗可防止与酒精相关的线粒体超氧化物产生、线粒体 DNA 损伤和诱导型一氧化氮合酶诱导增加，但不会显着减轻脂肪变性。伴随着这些氧化损伤指标，SAM 可以防止酒精介导的细胞色素 c 氧化酶亚基损失，如蓝色天然 PAGE 蛋白质组学和免疫印迹分析所示，从而部分保留了复合物 IV 活性。 SAM 治疗减弱了线粒体应激伴侣抑制蛋白的上调。尽管补充 SAM 本身并不能缓解脂肪变性，但 SAM 可以预防酒精介导的线粒体基因组和蛋白质组的几个关键缺陷，这些缺陷会导致饮酒后肝脏的生物能缺陷。这些发现揭示了新的分子靶点，SAM 可能通过这些靶点减轻酒精性肝损伤的一个关键因素：线粒体功能障碍。
An early event that occurs in response to alcohol consumption is mitochondrial dysfunction, which is evident in changes to the mitochondrial proteome, respiration defects, and mitochondrial DNA (mtDNA) damage. S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive oxygen/nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial superoxide production, mtDNA damage, and inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of oxidant damage, SAM prevented alcohol-mediated losses in cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury: mitochondria dysfunction.