Aerobic respiration, although metabolically advantageous in O2-rich environments, can be detrimental to the cell when O2 is not fully reduced resulting in cytotoxic reactive oxygen species (ROS) production. Cytochrome c oxidase subunit 4 (COX-4) is primarily responsible for fully reducing O2 during metabolism and exists as COX4-1 and COX4-2 isoforms. The former exists in normoxia, but is replaced by the latter in hypoxia. This change is brought about by two mechanisms, the first involving regulation by hypoxia inducible factor 1 (HIF-1), which directly upregulates COX4-2 and indirectly degrades COX4-1. The second mechanism involves an oxygen responsive element (ORE), which upregulates COX4-2 in a HIF-1 independent manner. The convergence of two unrelated pathways to regulate COX4-1 and COX4-2 would allow cells to optimize their metabolic profile within an environment experiencing varying O2, such as Earth’s early atmosphere in the case of primitive aerobic bacteria or in multicellular organisms where O2 levels vary between tissues such as lung tissue.

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