Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland and Detroit, MI 48201, USA.
Cells. 2021 Jan 20;10(2):197. doi: 10.3390/cells10020197.
Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome , pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein-protein interactions. The twin CXC family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CXC motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CXC proteins in the mitochondria via COX assembly and control of its activity through protein-protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CXC protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease.
氧化磷酸化是哺乳动物中一种紧密调节的过程，发生在内、外线粒体膜上，由电子传递链和 ATP 合酶组成。复合物 IV，又称细胞色素 c 氧化酶 (COX)，是电子传递链的末端酶，负责从细胞色素 c 接受电子，泵出质子以促进 ATP 合酶利用的梯度产生 ATP，并将氧气还原为水。因此，COX 通过许多机制进行紧密调节，包括蛋白质-蛋白质相互作用。最近的研究表明，双 CXC 蛋白家族通过协助复合物组装、生物发生和活性参与 COX 调节。双 CXC 基序允许这些蛋白质使用 Mia40/CHCHD4 的氧化还原导入机制进入线粒体的膜间空间。研究表明，在从酵母到人类细胞的实验模型中，敲低本文讨论的蛋白质会导致有氧呼吸减少或完全缺乏，因为这些蛋白质在物种间是保守的。本文强调并讨论了双 CXC 蛋白通过 COX 组装对线粒体中 COX 调节的重要性，以及通过蛋白质-蛋白质相互作用对其活性的控制，进一步受细胞信号通路调节。有趣的是，CXC 蛋白家族的某些成员，包括 MNRR1 和 CHCHD10，具有一个新的特征，即它们不仅定位于线粒体，还定位于细胞核，在那里它们介导氧和应激诱导的转录调节，为线粒体-核串扰及其在人类疾病中的参与开辟了新的视角。
