Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation.
Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation.
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DOI：
10.1111/acer.13473
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Fritz KS
中科院分区：
文献类型：
--
作者：
Assiri MA;Roy SR;Harris PS;Ali H;Liang Y;Shearn CT;Orlicky DJ;Roede JR;Hirschey MD;Backos DS;Fritz KS
慢性酒精消费是全球肝病的主要原因。氧化应激是酒精代谢的已知后果，被认为是酒精性肝病(ALD)的重要原因。因此，阐明导致持续氧化应激和下游氧化还原失衡的途径可能揭示乙醇消费如何导致ALD。最近的研究表明，乙醇代谢通过一些蛋白质组的改变影响线粒体的抗氧化过程，包括关键抗氧化蛋白的超乙酰化。为了阐明乙醇诱导的肝脏氧化应激的机制，我们在6周酒精摄入的Lieber-DeCarli小鼠模型上研究了蛋白质超乙酰化在调节线粒体超氧化物歧化酶(SOD2)结构和功能中的作用。我们的实验方法包括免疫印迹、免疫组织化学、活性分析、质谱学和电子计算机建模。我们发现，乙醇代谢显著增加了SOD2在两个功能相关的赖氨酸位点K68和K122的乙酰化，导致酶活性下降40%，而SOD2的总体丰度没有变化。体外研究还揭示了哪些赖氨酸残基更容易发生乙酰化。免疫组织化学分析表明，SOD2的高乙酰化发生在肝脏内的第3区附近，这是肝脏主要的乙醇代谢区域。总体而言，这项研究中提出的发现支持乙醇诱导的赖氨酸乙酰化作为线粒体内的一种不利的翻译后修饰，直接影响SOD2的电荷状态和活性。最后，本文提供的数据表明，由于慢性乙醇代谢，蛋白质超乙酰化可能是导致肝脏氧化还原平衡失衡的主要因素。
Chronic ethanol consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of ethanol metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how ethanol consumption leads to ALD. Recent studies suggest that ethanol metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins. In order to elucidate mechanisms of ethanol-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of ethanol consumption. Our experimental approach includes immunoblotting, immunohistochemistry, activity assays, mass spectrometry, and in silico modeling. We found that ethanol metabolism significantly increased the acetylation of SOD2 at two functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. Immunohistochemical analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main ethanol-metabolizing region of the liver. Overall, the findings presented in this study support a role for ethanol-induced lysine acetylation as an adverse post-translational modification within the mitochondria that directly impacts SOD2 charge-state and activity. Lastly, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic ethanol metabolism.
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影响因子：
4.1
作者：
Harris PS;Gomez JD;Backos DS;Fritz KS
通讯作者：
Fritz KS
DOI：
10.4103/0973-7847.70902
发表时间：
2010-07
期刊：
Pharmacognosy reviews
影响因子：
--
作者：
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影响因子：
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作者：
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影响因子：
7.7
作者：
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通讯作者：
Xiong, Yue
DOI：
10.1016/j.bbrc.2015.12.037
发表时间：
2016-04-08
影响因子：
3.1
作者：
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