Hyperacetylation of Cardiac Mitochondrial Proteins Is Associated with Metabolic Impairment and Sirtuin Downregulation after Chronic Total Body Irradiation of ApoE-/- Mice
Hyperacetylation of Cardiac Mitochondrial Proteins Is Associated with Metabolic Impairment and Sirtuin Downregulation after Chronic Total Body Irradiation of ApoE-/- Mice
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DOI：
10.3390/ijms20205239
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发表时间：
2019-10-02
影响因子：
5.6
通讯作者：
Azimzadeh, Omid
中科院分区：
文献类型：
--
作者：
Barjaktarovic, Zarko;Merl-Pham, Juliane;Azimzadeh, Omid
长期暴露于低剂量电离辐射与心血管疾病风险增加有关。能量代谢的改变被认为有助于辐射引起的心脏病理，线粒体功能障碍是这种疾病的一个标志。本研究的目的是探讨乙酰化在心脏线粒体对慢性辐射的长期反应中的调节作用。apoe缺陷的C57Bl/6J小鼠接受低剂量率（20毫戈瑞/天）γ辐射300天，导致累积总剂量为6.0戈瑞。分离心脏线粒体并进行定量蛋白质组学分析。通过免疫印迹、酶活性测定和ELISA进一步验证辐射诱导的蛋白质组和乙酰组改变。总共有71个蛋白在辐照后显示出乙酰化状态改变的肽。绝大多数（94%）的高乙酰化蛋白参与TCA循环、脂肪酸氧化、氧化应激反应和sirtuin途径。升高的乙酰化模式与线粒体sirtuins活性降低、乙酰辅酶a水平升高相吻合，并伴有主要心脏代谢调节因子PGC-1 α和PPAR α的失活。这些观察结果表明，辐照后线粒体乙酰化的变化与心脏代谢的损害有关。我们提出了一种涉及慢性照射后晚期心脏损伤发展的新机制。
Chronic exposure to low-dose ionizing radiation is associated with an increased risk of cardiovascular disease. Alteration in energy metabolism has been suggested to contribute to radiation-induced heart pathology, mitochondrial dysfunction being a hallmark of this disease. The goal of this study was to investigate the regulatory role of acetylation in heart mitochondria in the long-term response to chronic radiation. ApoE-deficient C57Bl/6J mice were exposed to low-dose-rate (20 mGy/day) gamma radiation for 300 days, resulting in a cumulative total body dose of 6.0 Gy. Heart mitochondria were isolated and analyzed using quantitative proteomics. Radiation-induced proteome and acetylome alterations were further validated using immunoblotting, enzyme activity assays, and ELISA. In total, 71 proteins showed peptides with a changed acetylation status following irradiation. The great majority (94%) of the hyperacetylated proteins were involved in the TCA cycle, fatty acid oxidation, oxidative stress response and sirtuin pathway. The elevated acetylation patterns coincided with reduced activity of mitochondrial sirtuins, increased the level of Acetyl-CoA, and were accompanied by inactivation of major cardiac metabolic regulators PGC-1 alpha and PPAR alpha. These observations suggest that the changes in mitochondrial acetylation after irradiation is associated with impairment of heart metabolism. We propose a novel mechanism involved in the development of late cardiac damage following chronic irradiation.