A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4
A mitochondrial phosphatase required for cardiolipin biosynthesis: the PGP phosphatase Gep4
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DOI：
10.1038/emboj.2010.98
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发表时间：
2010-06-16
期刊：
影响因子：
11.4
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Osman, Christof;Haag, Mathias;Langer, Thomas
心磷脂（Cardiolipin，CL）是一种主要存在于线粒体膜上的独特的二聚磷酸甘油脂，对细胞能量代谢、线粒体动力学和启动凋亡途径具有重要作用。线粒体CL代谢紊乱导致Barth综合征患者心肌病在这里，我们确定了一种新的磷酸酶在线粒体基质空间，Gep 4，并证明它去磷酸化磷脂酰甘油磷酸产生磷脂酰甘油，在CL生物合成的一个重要步骤。大肠杆菌磷酸酶PgpA的一种神经靶向变体的表达恢复了Gep 4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生物合成中间体的鉴定，使我们能够将Gep 4整合到CL生物合成途径中，并在CL合成的早期步骤中将一个重要功能分配给Tam 41，Tam 41以前已被证明对维持正常CL水平至关重要。我们的实验提供了进一步解剖的机制，需要在线粒体中的CL水平的积累和维护的框架。EMBO Journal（2010）29，1976-1987。doi：10.1038/doj.2010.98; 2010年5月18日在线发布
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. The EMBO Journal (2010) 29, 1976-1987. doi: 10.1038/emboj.2010.98; Published online 18 May 2010