A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3
A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3
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DOI：
10.1042/bcj20170416
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发表时间：
2017-11-15
影响因子：
4.1
通讯作者：
Kastaniotis, Alexander J.
中科院分区：
文献类型：
--
作者：
Monteuuis, Geoffray;Suomi, Fumi;Kastaniotis, Alexander J.
线粒体脂肪酸合成（mtFAS）是一个高度保守的线粒体生物合成途径。线粒体FAS过程是线粒体呼吸链组装和功能所必需的，是几种线粒体酶复合物功能不可或缺的硫辛酸辅因子的合成所必需的，也是小鼠胚胎发育所必需的。人类mtFAS的突变已被报道会导致神经退行性疾病。哺乳动物mtFAS的丙二酰辅酶A来源仍不清楚。我们报告的一个保守的脊椎动物线粒体亚型ACC 1的ACACA转录剪接变异体表达的鉴定。小鼠细胞中相应转录物的特异性敲低（KD），或人细胞中CRISPR/Cas9介导的推定线粒体靶向序列的失活，导致脂酰化和线粒体片段化减少。同时KD的ACSF 3，编码线粒体丙二酰辅酶A合成酶先前牵连在mtFAS过程中，导致几乎完全消融蛋白质脂酰化，表明这些酶在mtFAS中有冗余的功能。硫辛酸合成所需的ACC 1的线粒体亚型的发现对于我们理解线粒体疾病、线粒体生物发生的代谢调节和癌症具有有趣的后果。
Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved pathway essential for mitochondrial biogenesis. The mtFAS process is required for mitochondrial respiratory chain assembly and function, synthesis of the lipoic acid cofactor indispensable for the function of several mitochondrial enzyme complexes and essential for embryonic development in mice. Mutations in human mtFAS have been reported to lead to neurodegenerative disease. The source of malonyl-CoA for mtFAS in mammals has remained unclear. We report the identification of a conserved vertebrate mitochondrial isoform of ACC1 expressed from an ACACA transcript splicing variant. A specific knockdown (KD) of the corresponding transcript in mouse cells, or CRISPR/Cas9-mediated inactivation of the putative mitochondrial targeting sequence in human cells, leads to decreased lipoylation and mitochondrial fragmentation. Simultaneous KD of ACSF3, encoding a mitochondrial malonyl-CoA synthetase previously implicated in the mtFAS process, resulted in almost complete ablation of protein lipoylation, indicating that these enzymes have a redundant function in mtFAS. The discovery of a mitochondrial isoform of ACC1 required for lipoic acid synthesis has intriguing consequences for our understanding of mitochondrial disorders, metabolic regulation of mitochondrial biogenesis and cancer.