Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with pleiotropic complex I defects. Using complexome profiling and biochemical analyses, we have explored the structural rearrangements of the respiratory chain in human cell lines depleted of the catalytic complex IV subunit COX1 or COX2. In the absence of a functional complex IV holoenzyme, several supercomplex I+III₂ species coexist, which differ in their content of COX subunits and COX7A2L/HIGD2A assembly factors. The incorporation of an atypical COX1‐HIGD2A submodule attenuates supercomplex I+III₂ turnover rate, indicating an unexpected molecular adaptation for supercomplexes stabilization that relies on the presence of COX1 independently of holo‐complex IV formation. Our data set the basis for complex I structural dependence on complex IV, revealing the co‐existence of alternative pathways for the biogenesis of “supercomplex‐associated” versus individual complex IV, which could determine physiological adaptations under different stress and disease scenarios.

中文翻译：

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多种途径可协调人线粒体复合物IV的组装和呼吸超复合物的稳定。

线粒体呼吸链复合物I，III和IV可以缔合称为较大复合物或呼吸小体的较大结构，从而在各个复合物之间产生结构上的相互依存关系，尚待了解。在患者中，复杂的IV亚基基因中的无意义突变会导致严重的脑肌病，随机伴有多效性复杂的I型缺陷。使用复杂的基因组分析和生化分析，我们已经探索了人类细胞系中的呼吸链的结构重排，该细胞系中缺少催化复杂的IV亚基COX1或COX2。在没有功能性复合物IV全酶的情况下，几种超复合物I + III ₂物种共存，它们在COX亚基和COX7A2L / HIGD2A组装因子上的含量不同。非典型COX1-HIGD2A子模块的加入减弱了超复合物I + III _2的转化率，表明超复合物稳定的意想不到的分子适应性依赖于COX1的存在而与全络合物IV的形成无关。我们的数据为复杂I对复杂IV的结构依赖奠定了基础，揭示了“超级复杂相关”与单个复杂IV的生物合成的替代途径的共存，这可以确定在不同压力和疾病情况下的生理适应性。