The assembly pathways of mitochondrial respirasome (supercomplex I+III+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (P-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of P-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.
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Article Synopsis
- * Researchers created knockin mice with normal respiratory complex levels but reduced respirasome levels to study its role in living organisms.
- * Surprisingly, these mice remained healthy and maintained normal energy levels and exercise capacity, suggesting that high levels of respirasomes may not be necessary for basic bioenergetics, while also prompting further investigation into their potential functions, like protein stability and aging.
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