Hypoxia. 2. Hypoxia regulates cellular metabolism

Abstract

Adaptation to lowering oxygen levels (hypoxia) requires coordinated downregulation of metabolic demand and supply to prevent a mismatch in ATP utilization and production that might culminate in a bioenergetic collapse. Hypoxia diminishes ATP utilization by downregulating protein translation and the activity of the Na-K-ATPase. Hypoxia diminishes ATP production in part by lowering the activity of the electron transport chain through activation of the transcription factor hypoxia-inducible factor-1. The decrease in electron transport limits the overproduction of reactove oxygen species during hypoxia and slows the rate of oxygen depletion to prevent anoxia. In this review, we discuss these mechanisms that diminish metabolic supply and demand for adaptation to hypoxia.

Fig. 1.

Hypoxia activates hypoxia inducible factor-1 (HIF-1). HIF1α subunit is hydroxylated by pyruvate dehydrogenase 2 (PHD2) at distinct proline residues thereby targeting the protein for von Hippel-Lindau protein (pVHL)-mediated proteasomal degradation. Hypoxia concomitantly diminishes PHD2 activity and induces the production of mitochondrial reactive oxygen species (ROS) at complex III resulting in an inhibition of hydroxylation of HIF1α subunit. Once HIF1α subunit is stabilized, it binds with HIF-β and p300 coactivators to hypoxic response elements (HREs) in the promoters and enhancers of target genes that modulate metabolism.

Fig. 2.

HIF-1 shifts metabolism from oxidative to glycolysis. HIF-1 promotes the activation of glycolysis by upregulating numerous glycolytic genes including lactate dehydrogenase A (LDH-A), which converts pyruvate to lactate. Pyruvate conversion into acetyl-coA is dependent on PDH. HIF-1 also induces PDK1, a negative regulator of PDH. Thus HIF-1 diminishes pyruvate entry into the tricarboxylic acid (TCA) cycle and oxidative metabolism.

Fig. 3.

Hypoxia diminishes electron flux through the electron transport chain. Hypoxia diminishes respiratory activity by activating HIF-1, which increases micro-RNA 210 (miR-210), inducible nitric oxide synthase (iNOS), and switching of cytochrome c oxidase (COX)4–1 subunit to COX4–2. Hypoxia can also directly decrease complex IV (COX) activity.

Fig. 4.

Hypoxia diminishes cellular ATP demand. Protein translation and Na-K-ATPase are two major ATP-utilizing processes in the cell. Hypoxia through the generation of mitochondrial ROS activates AMP-activated protein kinase (AMPK) resulting in a decrease in Na-K-ATPase activity and inhibition of mammalian target of rapamycin (mTORC1)-dependent translation. Hypoxia also activates pancreatic eIF2α kinase (PERK) to dampen protein translation.

Fig. 5.

Hypoxia depresses the respiratory rate for metabolic adaptation. The downregulation of ATP demand and supply diminishes the respiratory rate, which prevents the overproduction of ROS and depletion of oxygen under hypoxic conditions.