Structural Biology Group, European Synchrotron Radiation Facility (ESRF), 71 avenue des Martyrs, 38043, Grenoble, France.
Institut de Biologie Structurale (IBS), CNRS, CEA, Université Grenoble Alpes, 71 avenue des Martyrs, 38044, Grenoble, France.
Angew Chem Int Ed Engl. 2021 Feb 23;60(9):4689-4697. doi: 10.1002/anie.202011548. Epub 2021 Jan 12.
Fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are mitochondrial redox processes that generate ATP. The biogenesis of the respiratory Complex I, a 1 MDa multiprotein complex that is responsible for initiating OXPHOS, is mediated by assembly factors including the mitochondrial complex I assembly (MCIA) complex. However, the organisation and the role of the MCIA complex are still unclear. Here we show that ECSIT functions as the bridging node of the MCIA core complex. Furthermore, cryo-electron microscopy together with biochemical and biophysical experiments reveal that the C-terminal domain of ECSIT directly binds to the vestigial dehydrogenase domain of the FAO enzyme ACAD9 and induces its deflavination, switching ACAD9 from its role in FAO to an MCIA factor. These findings provide the structural basis for the MCIA complex architecture and suggest a unique molecular mechanism for coordinating the regulation of the FAO and OXPHOS pathways to ensure an efficient energy production.
脂肪酸 β-氧化 (FAO) 和氧化磷酸化 (OXPHOS) 是产生 ATP 的线粒体氧化还原过程。负责启动 OXPHOS 的 1MDa 多蛋白复合物呼吸复合物 I 的生物发生是由组装因子介导的，包括线粒体复合物 I 组装 (MCIA) 复合物。然而，MCIA 复合物的组织和作用仍不清楚。在这里，我们表明 ECSIT 作为 MCIA 核心复合物的桥接节点发挥作用。此外，低温电子显微镜结合生化和生物物理实验表明，ECSIT 的 C 末端结构域直接与 FAO 酶 ACAD9 的退化脱氢酶结构域结合，并诱导其去黄素化，将 ACAD9 从其在 FAO 中的作用转变为 MCIA 因子。这些发现为 MCIA 复合物的结构提供了基础，并提出了一种独特的分子机制，用于协调 FAO 和 OXPHOS 途径的调节，以确保有效的能量产生。
