Abstract
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that regulates transcriptional activation of several genes responsive to the lack of oxygen, including erythropoietin, vascular endothelial growth factor, glycolytic enzymes, and glucose transporters. Because the involvement of mitochondria in the regulation of HIF-1 has been postulated, we tested the effects of mitochondrial electron transport chain deficiency on HIF-1 protein expression and DNA binding in hypoxic cells. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits electron transport chain at the level of complex I. MPTP is first converted to a pharmacologically active metabolite 1-methyl-4-phenylpyridinum (MPP+). MPP+ effectively inhibited both complex I activity and hypoxic accumulation of HIF-1alpha protein in dopaminergic cell lines PC12 and CATH.a. In C57BL/6 mice, a single dose of MPTP (15 mg/kg, intraperitoneal) inhibited complex I activity and HIF-1alpha protein accumulation in the striatum in response to a subsequent hypoxic challenge (8% O(2), 4 h). In a genetic model system, 40% complex I-inhibited human-ape xenomitochondrial cybrids, hypoxic induction of HIF-1alpha was severely reduced, and HIF-1 DNA binding was diminished. However, succinate, the mitochondrial complex II substrate, restored the hypoxic response in cybrid cells, suggesting that electron transport chain activity is required for activation of HIF-1. A partial complex I deficiency and a mild reduction in intact cell oxygen consumption effectively prevented hypoxic induction of HIF-1alpha protein.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
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1-Methyl-4-phenylpyridinium / pharmacology
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Animals
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Brain / drug effects
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Brain / metabolism
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DNA / genetics
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DNA / metabolism
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DNA, Mitochondrial / genetics
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Disease Models, Animal
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Electron Transport / drug effects
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Electron Transport Complex I
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Gene Expression Regulation* / drug effects
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Humans
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Hybrid Cells / drug effects
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Hybrid Cells / metabolism
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Mice, Inbred C57BL
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Mitochondria / drug effects
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Mitochondria / genetics
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Mitochondria / metabolism*
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NADH, NADPH Oxidoreductases / antagonists & inhibitors
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NADH, NADPH Oxidoreductases / deficiency
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NADH, NADPH Oxidoreductases / metabolism
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Neostriatum / drug effects
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Neostriatum / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxygen / metabolism*
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / genetics
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / pathology
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Primates
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Protein Binding / drug effects
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Succinic Acid / pharmacology
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Transcription Factors*
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Tumor Cells, Cultured
Substances
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DNA, Mitochondrial
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DNA-Binding Proteins
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Transcription Factors
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DNA
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Succinic Acid
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NADH, NADPH Oxidoreductases
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Electron Transport Complex I
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1-Methyl-4-phenylpyridinium
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Oxygen