Adaptation of OXPHOS biogenesis to cellular requirements

Metabolic cues regulate the formation of the mitochondrial OXPHOS machinery. These regulatory processes are tightly linked to mitochondrial translation, proteolytic degradation of unassembled subunits, and the formation of supercomplexes, creating checkpoints at which nutrient availability, oxygen tension, and signaling pathways remodel OXPHOS content and activity. In particular, the cytochrome c oxidase (COX) assembly pathway is regulated at multiple steps of its biogenesis in response to cellular demands. COX consists of mitochondrially encoded catalytic core subunits and nuclear-encoded accessory subunits whose coordinated expression, cofactor insertion, and incorporation into the COX enzyme result in optimized electron transport capacity. Consequently, COX assembly depends on numerous dedicated factors and protein isoforms, many of which are expressed in a tissue-specific manner. Through these metabolically regulated processes, cells tune oxidative phosphorylation efficiency, limit reactive oxygen species production, and support context-specific metabolic programs in development, adaptation, and disease.