Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions. Here, COXFA4 is linked to mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.