The biomedical relevance of the COX11, COX19, and PET191 protein interactomes is highlighted by mutations in CcO subunits COX1 and COX2 and the assembly factors PET191, SCO1, SCO2, COA6, COA3, COX14, COX10, COX15, COX16, COX20, and SURF1, causing devastating human mitochondrial cardio- and encephalomyopathies. Here, SCO1 is linked to mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.