Regulation of glucose and energy metabolism by Hypoxia-Inducible Factor 1


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Gregg Semenza

Johns Hopkins University School of Medicine, USA

Abstract

The transcription factor HIF-1 plays an essential role in the maintenance of oxygen homeostasis. HIF-1 is a heterodimer composed of an O2-regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. HIF-1α is continuously synthesized and degraded under normoxic conditions, whereas under hypoxic conditions, HIF-1α degradation is inhibited, the protein accumulates, dimerizes with HIF-1β, binds to cis-acting hypoxia response elements in target genes, and recruits co-activator proteins, leading to increased transcription. O2-dependent degradation of HIF-1α is triggered by binding of the von Hippel-Lindau tumor-suppressor protein (VHL), which recruits an E3 ubiquitin-ligase complex that ubiquitinates HIF-1α and targets it for degradation.

HIF-1 mediates multiple adaptive metabolic responses to hypoxia. First, expression of pyruvate dehydrogenase (PDH) kinase 1 (PDK1) is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl CoA. In combination with the lactate dehydrogenase A (LDHA), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl CoA to the tricarboxylic cycle, thus reducing the levels of NADH and FADH2 delivered to the electron transport chain. Second, the subunit composition of cytochrome c oxidase is altered in hypoxic cells by increased expression of the COX4-2 subunit and increased degradation of the COX4-1 subunit. Third, mitochondrial autophagy is induced by HIF-1-mediated expression of BNIP3 in response to chronic hypoxia. Fourth, mitochondrial biogenesis and O2 consumption are repressed in VHL-null renal carcinoma cells through HIF-1-mediated expression of MXI1, which inhibits MYC activity, thereby blocking the expression of PGC-1β a key regulator of mitochondrial biogenesis.