To summarize, our results contribute to the elucidation of the role of COX4-1 in metabolism and to the current understanding of the pathomechanism of COX deficiency due to nuclear-encoded subunits, and we conclude that COX4-2 is upregulated and partially rescues COX4-1 deficiency through HIF-1α activation induced by a yet-to-be-characterized, noncanonical pathway. This evidence concerns the gene COX4I2 and mitochondrial complex IV deficiency, nuclear-type.