The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that regulates transcriptional activation of several genes responsive to th e lack of oxygen, including erythropoietin, vascular endothelial growth fac tor, glycolytic enzymes, and glucose transporters. Because the involvement of mitochondria in the regulation of HIF-1 has been postulated, we tested t he effects of mitochondrial electron transport chain deficiency on HIF-1 pr otein expression and DNA binding in hypoxic cells. The neurotoxin 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits electron transport chai n at the level of complex I. MPTP is first converted to a pharmacologically active metabolite 1-methyl-4-phenylpyridinum (MPP+). MPP+ effectively inhi bited both complex I activity and hypoxic accumulation of HIF-1 alpha prote in in dopaminergic cell lines PC12 and CATH.a, In C57BL/6 mice, a single do se of MPTP (15 mg/kg, intraperitoneal) inhibited complex I activity and HIF -1 alpha protein accumulation in the striatum in response to a subsequent h ypoxic challenge (8% O-2, 4 h). In a genetic model system, 40% complex I-in hibited human-ape xe-nomitochondrial cybrids, hypoxic induction of HIF-1 al pha was severely reduced, and HIF-1 DNA binding was diminished. However, su ccinate, the mitochondrial complex II substrate, restored the hypoxic respo nse in cybrid cells, suggesting that electron transport chain activity is r equired for activation of HIF-1. A partial complex I deficiency and a mild reduction in intact cell oxygen consumption effectively prevented hypoxic i nduction of HIF-1 alpha protein.