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Regulation of mitochondrial proteostasis by the proton gradient
The EMBO Journal ( IF 11.4 ) Pub Date : 2022-08-01 , DOI: 10.15252/embj.2021110476
Maria Patron 1 , Daryna Tarasenko 2 , Hendrik Nolte 1 , Lara Kroczek 1 , Mausumi Ghosh 2, 3 , Yohsuke Ohba 1 , Yvonne Lasarzewski 1 , Zeinab Alsadat Ahmadi 4 , Alfredo Cabrera-Orefice 4 , Akinori Eyiama 1 , Tim Kellermann 1 , Elena I Rugarli 5, 6 , Ulrich Brandt 4, 5 , Michael Meinecke 2, 3 , Thomas Langer 1, 5
Affiliation  

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 Ca2+/H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ 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 Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.

中文翻译:

质子梯度对线粒体蛋白稳态的调节

线粒体适应不同的能量需求,重塑其蛋白质组。线粒体蛋白酶正在成为这些适应性过程的关键调节剂。在这里,我们使用多蛋白质组学方法来证明线粒体质子梯度对 m-AAA 蛋白酶 AFG3L2 的调节,将线粒体蛋白质转换与线粒体的能量状态相结合。我们将 TMBIM5(以前也称为 GHITM 或 MICS1)鉴定为线粒体内膜中的 Ca 2+ /H +交换剂,它结合并抑制 m-AAA 蛋白酶。TMBIM5 确保细胞存活和呼吸,允许 Ca 2+从线粒体流出并限制线粒体超极化。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 蛋白酶广泛地重塑线粒体蛋白质组并介导呼吸复合物 I 的蛋白水解分解,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 Ca 2+信号和线粒体的能量状态与蛋白质周转率整合在一起,从而重塑线粒体蛋白质组并调节细胞代谢。
更新日期:2022-08-01
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