Institute for Genetics, Centre for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
EMBO J. 2010 Jun 16;29(12):1976-87. doi: 10.1038/emboj.2010.98. Epub 2010 May 18.
Cardiolipin (CL), a unique dimeric phosphoglycerolipid predominantly present in mitochondrial membranes, has pivotal functions for the cellular energy metabolism, mitochondrial dynamics and the initiation of apoptotic pathways. Perturbations in the mitochondrial CL metabolism cause cardiomyopathy in Barth syndrome. Here, we identify a novel phosphatase in the mitochondrial matrix space, Gep4, and demonstrate that it dephosphorylates phosphatidylglycerolphosphate to generate phosphatidylglycerol, an essential step during CL biosynthesis. Expression of a mitochondrially targeted variant of Escherichia coli phosphatase PgpA restores CL levels in Gep4-deficient cells, indicating functional conservation. A genetic epistasis analysis combined with the identification of intermediates of CL biosynthesis allowed us to integrate Gep4 in the CL-biosynthetic pathway and assign an essential function during early steps of CL synthesis to Tam41, which has previously been shown to be essential for the maintenance of normal CL levels. Our experiments provide the framework for the further dissection of mechanisms that are required for accumulation and maintenance of CL levels in mitochondria.
心磷脂（CL）是一种主要存在于线粒体膜中的独特二聚磷酸甘油酯，对于细胞能量代谢、线粒体动力学和凋亡途径的启动具有关键作用。线粒体 CL 代谢的紊乱会导致巴特斯综合征的心肌病。在这里，我们鉴定出一种新型的线粒体基质空间磷酸酶 Gep4，并证明它可以将磷脂酰甘油磷酸去磷酸化为磷脂酰甘油，这是 CL 生物合成过程中的一个关键步骤。表达一种靶向线粒体的大肠杆菌磷酸酶 PgpA 的变体可以恢复 Gep4 缺陷细胞中的 CL 水平，表明功能保守。遗传上位性分析结合 CL 生物合成中间产物的鉴定，使我们能够将 Gep4 整合到 CL 生物合成途径中，并在 CL 合成的早期步骤中赋予 Tam41 一个必需的功能，此前已经证明 Tam41 对于维持正常的 CL 水平是必需的。我们的实验为进一步解析积累和维持线粒体中 CL 水平所需的机制提供了框架。
