Mitochondrial respiratory chain (MRC) enzymes associate in supercomplexes (SCs) that are structurally interdependent. This may explain why defects in a single component often produce combined enzyme deficiencies in patients. A case in point is the alleged destabilization of complex I in the absence of complex III. To clarify the structural and functional relationships between complexes, we have used comprehensive proteomic, functional, and biogenetical approaches to analyze a MT-CYB-deficient human cell line. We show that the absence of complex III blocks complex I biogenesis by preventing the incorporation of the NADH module rather than decreasing its stability. In addition, complex IV subunits appeared sequestered within complex III subassemblies, leading to defective complex IV assembly as well. Therefore, we propose that complex III is central for MRC maturation and SC formation. Our results challenge the notion that SC biogenesis requires the pre-formation of fully assembled individual complexes. In contrast, they support a cooperative-assembly model in which the main role of complex III in SCs is to provide a structural and functional platform for the completion of overall MRC biogenesis.

中文翻译：

---

呼吸超级复合物充当复合物 III 介导的人类线粒体复合物 I 和 IV 成熟的平台。


线粒体呼吸链 (MRC) 酶与结构上相互依赖的超级复合物 (SC) 结合。这可以解释为什么单一成分的缺陷常常会导致患者出现复合酶缺乏症。一个恰当的例子是，据称在缺乏复合物 III 的情况下复合物 I 会不稳定。为了阐明复合物之间的结构和功能关系，我们使用综合蛋白质组学、功能和生物遗传学方法来分析 MT-CYB 缺陷的人类细胞系。我们证明，复合物 III 的缺失通过阻止 NADH 模块的掺入而不是降低其稳定性来阻止复合物 I 的生物发生。此外，复杂 IV 亚基似乎被隔离在复杂 III 子组件内，也导致复杂 IV 组件有缺陷。因此，我们认为复合体 III 对于 MRC 成熟和 SC 形成至关重要。我们的结果挑战了 SC 生物发生需要预先形成完全组装的单个复合物的观念。相比之下，他们支持合作组装模型，其中复杂 III 在 SC 中的主要作用是为完成整个 MRC 生物发生提供结构和功能平台。