Figure 2.

Regulation of mitochondrial function and abundance by HIF-α. (A) To adapt to low oxygen tension, cells undergo two HIF-1α-mediated alterations of cellular metabolism: O₂-independent ATP production and reduction of mitochondrial O₂ consumption. HIF-1α signaling also contributes to the Warburg effect of aerobic glycolysis—that is, an uncoupling of glycolysis from O₂ levels—by stimulating the expression of the glucose transporter GLUT1 and glycolytic enzymes. Increased glycolysis generates increased levels of pyruvate, which is largely converted to lactate by HIF-inducible lactate dehydrogenase A (LDHA) and removed from the cell by the monocarboxylate transporter 4 (MCT4). HIF-1α induces pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and blocks conversion of pyruvate to acetyl-CoA, resulting in decreased flux through the tricarboxylic acid (TCA) cycle. Decreased TCA cycle activity attenuates oxidative phosphorylation and excessive mitochondrial ROS production. Under normoxia, COX4-1 is the predominant isoform of COX4 present in complex IV of the electron transport chain, which transfers electrons to O₂. Under hypoxia, HIF-1α upregulates the expression of COX4-2 and the mitochondrial protease LONP1, which in turn degrades COX4-1. COX4-2 is more efficient at facilitating the electron transfer to O₂ and thereby protects the cell from oxidative damage during hypoxia. (B) Control of mitochondrial biogenesis by HIF-α. HIF-1α induces the expression of MAX-interacting protein 1 (MXI1), a repressor of MYC activity, and thereby represses a subset of MYC target genes such as PGC-1β. HIF-1α-dependent activation of FOXO3a inhibits MYC activity by reducing MYC protein stability. Interaction between PGC-1 and transcription factors such as PPARα, ERR, and NRF-1/2 orchestrates the major functions of mitochondria. HIF-1α-mediated inhibition of MYC and PGC-1 results in reduced mitochondrial biogenesis.