Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1 - PubMed (original) (raw)
Review
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1
Gregg L Semenza. Biochem J. 2007.
Abstract
The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at Complex III, results in the increased generation of ROS (reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl-CoA. In combination with the hypoxia-induced expression of LDHA (lactate dehydrogenase A), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of NADH and FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions. Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.
Similar articles
- HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells.
Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. Fukuda R, et al. Cell. 2007 Apr 6;129(1):111-22. doi: 10.1016/j.cell.2007.01.047. Cell. 2007. PMID: 17418790 - HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. Kim JW, et al. Cell Metab. 2006 Mar;3(3):177-85. doi: 10.1016/j.cmet.2006.02.002. Cell Metab. 2006. PMID: 16517405 - HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. Papandreou I, et al. Cell Metab. 2006 Mar;3(3):187-97. doi: 10.1016/j.cmet.2006.01.012. Cell Metab. 2006. PMID: 16517406 - Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species.
Bell EL, Chandel NS. Bell EL, et al. Essays Biochem. 2007;43:17-27. doi: 10.1042/BSE0430017. Essays Biochem. 2007. PMID: 17705790 Review. - Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging.
Wei YH, Wu SB, Ma YS, Lee HC. Wei YH, et al. Chang Gung Med J. 2009 Mar-Apr;32(2):113-32. Chang Gung Med J. 2009. PMID: 19403001 Review.
Cited by
- Alterations in mitochondrial function in cardiac hypertrophy and heart failure.
Osterholt M, Nguyen TD, Schwarzer M, Doenst T. Osterholt M, et al. Heart Fail Rev. 2013 Sep;18(5):645-56. doi: 10.1007/s10741-012-9346-7. Heart Fail Rev. 2013. PMID: 22968404 Review. - Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis.
Clayton SA, MacDonald L, Kurowska-Stolarska M, Clark AR. Clayton SA, et al. Front Immunol. 2021 Apr 29;12:673916. doi: 10.3389/fimmu.2021.673916. eCollection 2021. Front Immunol. 2021. PMID: 33995417 Free PMC article. Review. - MiR-210--micromanager of the hypoxia pathway.
Huang X, Le QT, Giaccia AJ. Huang X, et al. Trends Mol Med. 2010 May;16(5):230-7. doi: 10.1016/j.molmed.2010.03.004. Epub 2010 Apr 29. Trends Mol Med. 2010. PMID: 20434954 Free PMC article. Review. - Does Hypoxia Decrease the Metabolic Rate?
Gu C, Jun JC. Gu C, et al. Front Endocrinol (Lausanne). 2018 Nov 13;9:668. doi: 10.3389/fendo.2018.00668. eCollection 2018. Front Endocrinol (Lausanne). 2018. PMID: 30555410 Free PMC article. Review. - Marine Natural Products as Inhibitors of Hypoxic Signaling in Tumors.
Nagle DG, Zhou YD. Nagle DG, et al. Phytochem Rev. 2009 Jun;8(2):415-429. doi: 10.1007/s11101-009-9120-1. Phytochem Rev. 2009. PMID: 20622986 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous