Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
Dev Cell. 2024 Apr 22;59(8):1043-1057.e8. doi: 10.1016/j.devcel.2024.02.011. Epub 2024 Mar 19.
Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the Mitochondrial Regulatory hub for respiratory Assembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.
蛋白质化学计量的控制对于细胞功能至关重要。线粒体氧化磷酸化（OXPHOS）呈现出复杂的化学计量挑战，因为电子传递链（ETC）和 ATP 合酶的比例必须严格控制，并且组装需要协调整合核基因组和线粒体基因组编码的蛋白质。如何实现正确的 OXPHOS 化学计量尚不清楚。我们确定了线粒体呼吸组装调节枢纽（MiRA）平台，该平台在酵母中同步 ETC 和 ATP 合酶的生物发生。从分子水平上看，这是通过一种停止-前进机制实现的：未被表征的蛋白质 Mra1 阻碍复合物 IV 的组装。组装进展需要两个“前进”信号：复合物 IV 组装因子 Rcf2 的结合以及 Mra1 与 Atp9 翻译的线粒体核糖体的相互作用，诱导 Mra1 降解，从而允许复合物 IV 和 ATP 合酶的同步成熟。停止-前进机制的失败会导致细胞死亡。MiRA 控制 OXPHOS 组装，确保由两个不同基因组编码的蛋白质机器具有正确的化学计量。
