The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (
cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at
Complex III, results in the increased generation of ROS (
reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (
pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial
enzyme that converts
pyruvate into
acetyl-CoA. In combination with the
hypoxia-induced expression of LDHA (
lactate dehydrogenase A), which converts
pyruvate into
lactate, PDK1 reduces the delivery of
acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of
NADH and
FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions.
Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to
hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial
protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.