Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis.
Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis.
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DOI：
10.1016/j.cmet.2011.04.007
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发表时间：
2011-06-08
期刊：
影响因子：
29
通讯作者：
Dixon JE
中科院分区：
文献类型：
--
作者：
Zhang J;Guan Z;Murphy AN;Wiley SE;Perkins GA;Worby CA;Engel JL;Heacock P;Nguyen OK;Wang JH;Raetz CR;Dowhan W;Dixon JE
PTPMT 1是第一个被发现定位于线粒体的蛋白质酪氨酸磷酸酶，但其生物学功能尚不清楚。在此，我们证明了小鼠体内Ptpmt 1的整体缺失导致胚胎死亡，这表明PTPMT 1在发育过程中起着不可或缺的作用。小鼠胚胎成纤维细胞中Ptpmt1缺陷损害线粒体呼吸并导致线粒体形态异常。Ptpmt 1缺陷成纤维细胞的脂质分析揭示了磷脂酰甘油磷酸（PGP）的积累沿着磷脂酰甘油的减少。PGP是心磷脂生物合成途径中的重要中间体，心磷脂是一种调节细胞器膜完整性和活性的细胞特异性磷脂。我们进一步证明了PTPMT 1在体外特异性地使PGP去磷酸化。PTPMT1的缺失导致心磷脂的急剧减少，这可以通过催化活性PTPMT1的表达而部分逆转。我们的研究确定PTPMT 1作为哺乳动物的PGP磷酸酶，并指出其作为心磷脂生物合成的调节剂的作用。
PTPMT1 was the first protein tyrosine phosphatase found localized to the mitochondria, but its biological function was unknown. Herein, we demonstrate that whole body deletion of Ptpmt1 in mice leads to embryonic lethality, suggesting an indispensable role for PTPMT1 during development. Ptpmt1-deficiency in mouse embryonic fibroblasts compromises mitochondrial respiration and results in abnormal mitochondrial morphology. Lipid analysis of Ptpmt1-deficient fibroblasts reveals an accumulation of phosphatidylglycerophosphate (PGP) along with a concomitant decrease in phosphatidylglycerol. PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis.
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