Medical Research Council, Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK; Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
Instituto de Investigación Hospital 12 de Octubre, Madrid 28041, Spain.
Cell Metab. 2022 Nov 1;34(11):1792-1808.e6. doi: 10.1016/j.cmet.2022.09.005. Epub 2022 Oct 4.
The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
线粒体呼吸链（MRC）的结构和功能组织仍存在激烈争议。在这里，我们展示了两种不同的 MRC 组织在人类细胞和有丝分裂后组织中共存，C-MRC 和 S-MRC，由三种 COX7A 亚基同工型（COX7A1/2 和 SCAFI）的优先表达来定义。COX7A 同工型促进不同共存 MRC 结构的功能重组，以防止代谢衰竭和 MRC 缺陷。值得注意的是，每种 MRC 组织的流行程度可通过丙酮酸脱氢酶复合物（PDC）的激活状态可逆调节。在氧化条件下，C-MRC 在生物能量学上更有效，而 S-MRC 在代谢重编程为糖酵解时优先维持氧化磷酸化（OXPHOS）。我们展示了汇聚在 PDC 的代谢特征与 MRC 的结构和功能组织之间的联系，挑战了 MRC 作为单一功能单元的广泛观点，并得出结论，其结构异质性需要对代谢功能进行最佳适应。
