钙依赖的 Mia40 诱导的 MICU1-MICU2 二聚体从 MCU 释放调节线粒体钙摄取。

The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake.

机构信息

Cellular Biochemistry, University of Kaiserslautern, Erwin-Schroedinger-Str. 13, 67663 Kaiserslautern, Germany; Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, 50674 Cologne, Germany.

Department of Biophysics, CIPMM, School of Medicine, University of Saarland, 66421, Homburg, Germany.

出版信息

Cell Metab. 2015 Oct 6;22(4):721-33. doi: 10.1016/j.cmet.2015.08.019. Epub 2015 Sep 17.

DOI:10.1016/j.cmet.2015.08.019

PMID:26387864

Abstract

The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.

摘要

主要的氧化还原酶 Mia40/CHCHD4 介导在线粒体膜间隙中二硫键的形成和蛋白质折叠。在这里，我们研究了 Mia40 的相互作用组，从而揭示了硫醇氧化与细胞凋亡、能量代谢和 Ca(2+)信号之间的联系。Mia40 的相互作用伙伴之一是 MICU1-线粒体 Ca(2+)单向转运体（MCU）的调节剂，它将 Ca(2+)穿过内膜。我们检查了 MICU1 的生物发生，发现 Mia40 引入了一个分子间二硫键，将 MICU1 和其抑制性同源物 MICU2 连接成异二聚体。缺乏这个二硫键会导致受体诱导的线粒体 Ca(2+)摄取增加。在二硫键存在的情况下，MICU1-MICU2 异二聚体与 MCU 的结合受 Ca(2+)水平的控制：二聚体在低 Ca(2+)水平下与 MCU 结合，在高 Ca(2+)浓度下解离。我们的发现支持这样一种模型，即线粒体 Ca(2+)摄取受单向转运体复合物的 Ca(2+)依赖性重塑调节。