Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.
Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, 50931, Cologne, Germany.
Nat Commun. 2020 Apr 2;11(1):1643. doi: 10.1038/s41467-020-15467-7.
Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation of dysfunctional CI arising from the inactivation of the N-module subunits due to attrition caused by its constant activity under physiological conditions. This CI salvage pathway maintains highly functional CI through a favorable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. Our results also identify ClpXP activity as an unforeseen target for therapeutic interventions in the large group of mitochondrial diseases characterized by the CI instability.
尽管对其结构和组装有了巨大的了解，但细胞色素 C 氧化酶（CI）这种最大的线粒体呼吸链复合物的周转率调控仍然是一个谜。在这里，我们报告说，CI 的 NADH 氧化的 N 模块以比复合物其余部分更高的速率并且在很大程度上独立于后者进行周转，这是由线粒体基质蛋白酶 ClpXP 完成的，它选择性地去除和降解受损的亚基。所观察到的机制似乎是一种防范措施，以防止由于 N 模块亚基的失活而导致的功能失调的 CI 积累，这种失活是由于其在生理条件下的持续活性而导致的磨损。这种 CI 挽救途径通过一种有利的机制维持了高度功能化的 CI，该机制比从头合成和重新组装整个 CI 所需的能量成本低得多。我们的结果还表明，ClpXP 活性是一大组以 CI 不稳定性为特征的线粒体疾病的治疗干预的意外靶标。
