Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
EMBO J. 2010 Sep 1;29(17):2888-98. doi: 10.1038/emboj.2010.169. Epub 2010 Jul 23.
The mitochondrial phospholipid metabolism critically depends on members of the conserved Ups1/PRELI-like protein family in the intermembrane space. Ups1 and Ups2 (also termed Gep1) were shown to regulate the accumulation of cardiolipin (CL) and phosphatidylethanolamine (PE), respectively, in a lipid-specific but coordinated manner. It remained enigmatic, however, how the relative abundance of both phospholipids in mitochondrial membranes is adjusted on the molecular level. Here, we describe a novel regulatory circuit determining the accumulation of Ups1 and Ups2 in the intermembrane space. Ups1 and Ups2 are intrinsically unstable proteins, which are degraded by distinct mitochondrial peptidases. The turnover of Ups2 is mediated by the i-AAA protease Yme1, whereas Ups1 is degraded by both Yme1 and the metallopeptidase Atp23. We identified Mdm35, a member of the twin Cx(9)C protein family, as a novel interaction partner of Ups1 and Ups2. Binding to Mdm35 ensures import and protects both proteins against proteolysis. Homologues to all components of this pathway are present in higher eukaryotes, suggesting that the regulation of mitochondrial CL and PE levels is conserved in evolution.
线粒体磷脂代谢严重依赖于跨膜间隙中保守的 Ups1/PRELI 样蛋白家族成员。Ups1 和 Ups2（也称为 Gep1）分别被证明以脂质特异性但协调的方式调节心磷脂 (CL) 和磷脂酰乙醇胺 (PE) 的积累。然而，在线粒体膜中两种磷脂的相对丰度如何在分子水平上进行调节仍然是个谜。在这里，我们描述了一个新的调控回路，该回路决定了 Ups1 和 Ups2 在跨膜间隙中的积累。Ups1 和 Ups2 是内在不稳定的蛋白质，它们被不同的线粒体肽酶降解。Ups2 的周转由 i-AAA 蛋白酶 Yme1 介导，而 Ups1 则由 Yme1 和金属肽酶 Atp23 共同降解。我们鉴定出 Mdm35 是 Ups1 和 Ups2 的一种新型相互作用伙伴，它是双 Cx(9)C 蛋白家族的成员。与 Mdm35 结合可确保导入并防止两种蛋白质被蛋白酶降解。该途径的所有成分的同源物都存在于高等真核生物中，这表明线粒体 CL 和 PE 水平的调节在进化中是保守的。
