Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2021 May 26;10:e67624. doi: 10.7554/eLife.67624.
Dysfunction of the mitochondrial electron transport chain (mETC) is a major cause of human mitochondrial diseases. To identify determinants of mETC function, we screened a genome-wide human CRISPRi library under oxidative metabolic conditions with selective inhibition of mitochondrial Complex III and identified ovarian carcinoma immunoreactive antigen (OCIA) domain-containing protein 1 (OCIAD1) as a Complex III assembly factor. We find that OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies. Our data indicate that OCIAD1 is required for maintenance of normal steady-state levels of Complex III and the proteolytic processing of the catalytic subunit cytochrome (CYC1). In OCIAD1 depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III. We propose that OCIAD1 acts as an adaptor within prohibitin assemblies to stabilize and/or chaperone CYC1 and to facilitate its proteolytic processing by the IMMP2L protease.
线粒体电子传递链（mETC）功能障碍是人类线粒体疾病的主要原因。为了确定 mETC 功能的决定因素，我们在选择性抑制线粒体复合物 III 的氧化代谢条件下筛选了全基因组人类 CRISPRi 文库，并鉴定出卵巢癌免疫反应性抗原（OCIA）结构域包含蛋白 1（OCIAD1）为复合物 III 组装因子。我们发现 OCIAD1 是一种线粒体内膜蛋白，它与超分子抑制素组装形成复合物。我们的数据表明，OCIAD1 对于维持复合物 III 的正常稳态水平和催化亚基细胞色素 c（CYC1）的蛋白水解加工是必需的。在 OCIAD1 耗尽的线粒体中，未加工的 CYC1 被半甲基化并掺入复合物 III。我们提出，OCIAD1 作为抑制素组装体中的接头，稳定和/或伴侣 CYC1，并促进其由 IMMP2L 蛋白酶进行蛋白水解加工。
