Max Planck Institute for Biology of Ageing, Cologne, Germany.
Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.
EMBO J. 2022 Aug 16;41(16):e110476. doi: 10.15252/embj.2021110476. Epub 2022 Aug 1.
Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca /H exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.
线粒体根据不同的能量需求重塑其蛋白质组以适应变化。线粒体蛋白酶作为这些适应性过程的关键调节因子正在逐渐被人们认识。在这里，我们采用多蛋白组学方法来研究线粒体质子梯度对 m-AAA 蛋白酶 AFG3L2 的调控，从而将线粒体蛋白质的周转与线粒体的能量状态联系起来。我们鉴定出线粒体内膜中的 TMBIM5（以前也称为 GHITM 或 MICS1）是一种 Ca2+/H+交换蛋白，它可以与 m-AAA 蛋白酶结合并抑制其活性。TMBIM5 确保细胞的存活和呼吸作用，使 Ca2+从线粒体中流出，并限制线粒体的超极化。然而，持续的超极化会触发 TMBIM5 的降解和 m-AAA 蛋白酶的激活。m-AAA 蛋白酶广泛重塑线粒体蛋白质组，并介导呼吸复合物 I 的蛋白水解断裂，以限制超极化线粒体中 ROS 的产生和氧化损伤。因此，TMBIM5 将线粒体 Ca2+信号和线粒体的能量状态与蛋白质周转率结合起来，重塑线粒体蛋白质组并调整细胞代谢。
