The Role of Mitochondria in the Regulation of Hypoxia-inducible Factor 1 Expression during Hypoxia
| Autor: | Paola Pichiule, Faton Agani, Juan C. Chavez, Joseph C. LaManna |
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| Rok vydání: | 2000 |
| Předmět: |
Primates
1-Methyl-4-phenylpyridinium Succinic Acid Hybrid Cells Mitochondrion Biology DNA Mitochondrial Biochemistry Electron Transport Mice chemistry.chemical_compound Parkinsonian Disorders Genetic model Tumor Cells Cultured Animals Humans Neurotoxin NADH NADPH Oxidoreductases Molecular Biology Transcription factor G alpha subunit Electron Transport Complex I MPTP Glucose transporter Brain Nuclear Proteins DNA Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Mitochondria DNA-Binding Proteins Mice Inbred C57BL Neostriatum Oxygen Disease Models Animal Gene Expression Regulation chemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Hypoxia-Inducible Factor 1 Protein Binding Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 275:35863-35867 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m005643200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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