哺乳动物丙二酰辅酶 A 合酶 ACSF3 是线粒体蛋白丙二酰化和代谢效率所必需的。
The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency.
机构信息
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Cell Chem Biol. 2017 Jun 22;24(6):673-684.e4. doi: 10.1016/j.chembiol.2017.04.009. Epub 2017 May 4.
Malonyl-coenzyme A (malonyl-CoA) is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, which produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing. ACSF3 KO cells exhibited elevated malonate and impaired mitochondrial metabolism. Unbiased and targeted metabolomics analysis of KO and control cells in the presence or absence of exogenous malonate revealed metabolic changes dependent on either malonate or malonyl-CoA. While ACSF3 was required for the metabolism and therefore detoxification of malonate, ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins. Together, these data describe an essential role for ACSF3 in dictating the metabolic fate of mitochondrial malonate and malonyl-CoA in mammalian metabolism.
丙二酰辅酶 A（malonyl-CoA）是哺乳动物脂肪酸生物化学中的一种中心代谢物，在细胞质中生成和利用；然而，对于非典型细胞器特异性的 malonyl-CoA 代谢知之甚少。线粒体中的 malonyl-CoA 是由 malonyl-CoA 合成酶 ACSF3 产生的，它将丙二酸盐（琥珀酸脱氢酶的内源性竞争性抑制剂）转化为 malonyl-CoA。为了确定线粒体 malonyl-CoA 的代谢需求，通过 CRISPR/Cas 介导的基因组编辑生成了 ACSF3 敲除 (KO) 细胞。ACSF3 KO 细胞表现出丙二酸盐升高和线粒体代谢受损。在存在或不存在外源丙二酸盐的情况下，对 KO 和对照细胞进行无偏和靶向代谢组学分析，揭示了依赖于丙二酸盐或 malonyl-CoA 的代谢变化。虽然 ACSF3 是丙二酸盐代谢和解毒所必需的，但 ACSF3 衍生的 malonyl-CoA 是线粒体蛋白赖氨酸丙二酰化所必需的。总之，这些数据描述了 ACSF3 在决定哺乳动物代谢中线粒体丙二酸盐和 malonyl-CoA 的代谢命运方面的重要作用。
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