Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation
Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation
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赖氨酸丙二酰化的蛋白质组学和生化研究表明其在线粒体功能和脂肪酸氧化中与丙二酸尿症相关的调节作用。
DOI：
10.1074/mcp.m115.048850
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发表时间：
2015-11-01
影响因子：
7
通讯作者：
Zhao, Yingming
中科院分区：
文献类型：
--
作者：
Colak, Gozde;Pougovkina, Olga;Zhao, Yingming
沉默调节蛋白5调节的赖氨酸丙二酰化（Kmal）的蛋白质底物仍然未知，阻碍了其功能分析。在这项研究中，我们进行了蛋白质组学筛选，确定了4042 Kmal位点上的1426蛋白在小鼠肝脏和4943 Kmal位点上的1822蛋白在人成纤维细胞。丙二酰辅酶A脱羧酶（MCD）缺陷细胞中丙二酰辅酶A水平的增加诱导底物蛋白中的Kmal水平。我们鉴定了461个Kmal位点，显示MCD缺乏反应增加2倍以上，以及1452个Kmal位点，仅在MCD-/-成纤维细胞中检测到，但在MCD+/+细胞中未检测到，表明Kmal在MCD缺乏中具有致病作用。赖氨酸丙二酰化增加的细胞显示线粒体功能受损和脂肪酸氧化，表明赖氨酸丙二酰化在丙二酸尿症的病理生理学中起作用。我们的研究建立了Kmal与遗传疾病之间的关联，并为阐明Kmal途径和丙二酰辅酶A对细胞生理学和人类疾病的贡献提供了丰富的资源。
The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.