Carta Acesso aberto Revisado por pares

Waiting to Inhale: HIF-1 Modulates Aerobic Respiration

2007; Cell Press; Volume: 129; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2007.03.031

ISSN

1097-4172

Autores

Adam T. Boutin, Randall S. Johnson,

Tópico(s)

Cardiovascular and Diving-Related Complications

Resumo

The hypoxia-inducible factor HIF-1 is known to promote anaerobic respiration during low oxygen conditions (hypoxia). In this issue, Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar expand the range of HIF-1's functions by showing that it modulates aerobic respiration as well. The hypoxia-inducible factor HIF-1 is known to promote anaerobic respiration during low oxygen conditions (hypoxia). In this issue, Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar expand the range of HIF-1's functions by showing that it modulates aerobic respiration as well. It has been known since the time of Pasteur that cells in low oxygen conditions switch from aerobic to anaerobic metabolism. More recently, it has become clear that the hypoxia-inducible factor 1 (HIF-1) is a key oxygen sensor that mediates the cell's ability to cope with decreased oxygen. HIF-1 is a transcriptional activator that is stabilized when oxygen concentrations in the cell are low. It upregulates glycolytic enzymes and glucose transporters, thereby allowing the cell to depend more heavily on the anaerobic process of glycolysis for energy. In this issue, Semenza and colleagues (Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar) reveal that HIF-1 unexpectedly also modulates aerobic metabolism. Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar show that in hypoxic conditions, the HIF-1 transcription factor regulates the replacement of a key subunit of the cytochrome oxidase complex (the last complex in the electron transport chain also known as complex IV) to maximize the efficiency of mitochondrial respiration. In this manner HIF-1 promotes the efficient use of available oxygen while also reducing the generation of harmful byproducts of respiration such as free radicals and H2O2. High-energy electrons from the tricarboxylic acid (TCA) cycle are passed through the four complexes of the electron transport chain, powering the buildup of a proton gradient across the mitochondrial inner membrane space. As part of complex IV, cytochrome oxidase transfers the electrons to oxygen. Complex IV resides in the inner mitochondrial membrane and is made up of 13 polypeptides (COX subunits), some of which have multiple isoforms and are subject to regulation. COX4 has two isoforms: COX4-1 and COX4-2. In an elegant study in mammalian cells, Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar specifically describe how the composition of complex IV changes in the face of low oxygen. The authors showed that during hypoxia, HIF-1 upregulates COX4-2 expression while also activating the gene for the LON mitochondrial protease, which in turn degrades COX4-1. This facilitates the swapping of subunit COX4-1 for the more efficient subunit COX4-2, thereby enhancing mitochondrial respiration (Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar; Figure 1). The enhancement of mitochondrial respiration during hypoxia by swapping cytochrome oxidase subunits has been demonstrated previously in yeast (Waterland et al., 1991Waterland R.A. Basu A. Chance B. Poyton R.O. J. Biol. Chem. 1991; 266: 4180-4186Abstract Full Text PDF PubMed Google Scholar, Allen et al., 1995Allen L.A. Zhao X.J. Caughey W. Poyton R.O. J. Biol. Chem. 1995; 270: 110-118Crossref PubMed Scopus (81) Google Scholar). However, the mechanism that mediates the swapping in yeast does not hinge on HIF-1, and there is in fact no HIF-1 homolog in yeast. The mechanism in yeast is tied to oxygen concentration more indirectly: the Hap2/3/4/5 and Hap1 proteins are activated by binding heme, and heme is only produced in aerobic conditions. Hap2/3/4/5, in turn, transactivates the COX5 isoform COX5a (COX5 is the yeast counterpart of mammalian COX4). At the same time, Hap1 activates Rox1, which represses the COX5b isoform. So in normal oxygen conditions, the less efficient COX5a predominates. During hypoxia, the activation of COX5a is lost, and the repression of COX5b is relieved. Thus, the more efficient subunit COX5b takes over for COX5a to enhance respiration during hypoxia (Burke and Poyton, 1998Burke P.V. Poyton R.O. J. Exp. Biol. 1998; 201: 1163-1175Crossref PubMed Google Scholar). The mammalian version described by Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar is similar in concept and involves the same two homologous subunits of complex IV but is regulated quite differently. However, the end result is a clear example of convergent evolution within the community of single and multicellular eukaryotes. Tumors are able to survive in hypoxic conditions, and pharmacological inhibition of HIF-1 is being explored currently as an anticancer therapy. Inhibition of the subunit switch described by Fukuda et al., 2007Fukuda R. Zhang H. Kim J.-W. Shimoda L. Dang C.V. Semenza G.L. Cell. 2007; (this issue)Google Scholar could be used therapeutically to further inhibit a tumor's ability to survive in hypoxia. More specifically, one could inhibit or inactivate COX4-2 and/or the LON protease to achieve strategic modulation of tumor metabolism. The data presented here nicely complement that published last year showing that HIF-1 expression increased pyruvate dehydrogenase kinase levels, acting to inhibit pyruvate dehydrogenase and thus prevent entry of pyruvate into the TCA cycle (Kim et al., 2006Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (2334) Google Scholar, Papandreou et al., 2006Papandreou I. Cairns R.A. Fontana L. Lim A.L. Danko N.C. Cell Metab. 2006; 3: 187-197Abstract Full Text Full Text PDF PubMed Scopus (1470) Google Scholar). Thus, it is clear that HIF-1 is acting across the metabolic spectrum, increasing glucose transport into the cell, ramping up glycolysis, and fine-tuning respiration in the mitochondria. What is perhaps most remarkable is that the same system responsible for this metabolic adaptation also modulates such a wide range of other organismal reactions to hypoxia, including physiological responses that arose much later in evolution, e.g., erythropoiesis and angiogenesis. One could argue that evolution found a very useful tool in HIF-1 early on and has continued to use it whenever short of breath. HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic CellsFukuda et al.CellApril 06, 2007In BriefO2 is the ultimate electron acceptor for mitochondrial respiration, a process catalyzed by cytochrome c oxidase (COX). In yeast, COX subunit composition is regulated by COX5a and COX5b gene transcription in response to high and low O2, respectively. Here we demonstrate that in mammalian cells, expression of the COX4-1 and COX4-2 isoforms is O2 regulated. Under conditions of reduced O2 availability, hypoxia-inducible factor 1 (HIF-1) reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation. Full-Text PDF Open Archive

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