HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.

By I. Papandreou, R. Cairns, Lucrezia Fontana, A. Lim, N. Denko. Cell Metabolism, 2006

2,267 citations recorded by the source corpus.

The HIF-1 transcription factor drives hypoxic gene expression changes that are thought to be adaptive for cells exposed to a reduced-oxygen environment. For example, HIF-1 induces the expression of glycolytic genes. It is presumed that increased glycolysis is necessary to produce energy when low oxygen will not support oxidative phosphorylation at the mitochondria. However, we find that while HIF-1 stimulates glycolysis, it also actively represses mitochondrial function and oxygen consumption by inducing pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase from using pyruvate to fuel the mitochondrial TCA cycle. This causes a drop in mitochondrial oxygen consumption and results in a relative increase in intracellular oxygen tension. We show by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fc762a0d5a2b764dd3de22ba3cd1e1bff06659c9

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Citations in the corpus

Hypoxia and cancer (2007, background): “LDHA is the enzyme responsible for conversion of pyruvate to lactate, and PDK1 is an inhibitor of pyruvate dehydrogenase that feeds pyruvate into the tricarboxylic acid cycle and thus toward OXPHOS.”
The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α (2010, neutral): “On the other hand, Hif1a directly inhibits mitochondrial respiration by upregulating expression of the pyruvate dehydrogenase kinase (PDK) gene (Kim et al., 2006; Papandreou et al., 2006).”
AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo (2012, background): “This may appear to be counterintuitive, as HIF-1a-dependent upregulation of PDK1 under hypoxia is proposed to direct glucose-derived carbon away from the CAC (Kim et al., 2006; Papandreou et al., 2006).”
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia (2011, background): “, and PDK1 is a known target of HIF-1a that inhibits the activity of PDH through phosphorylatio”
Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer (2009, background): “Stabilization of the transcription factor, hypoxia-inducible factor-1a, in hypoxic cells enhances the expression of glucose transporters, glycolytic enzymes, and inhibitory kinases for the pyruvate dehydrogenase complex, all of which serve to increase the production of lactate from glucose (Semenza,”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “The expression of PDK is increased in many cancers as a result of increased activation of the transcription factor hypoxia-inducible factor (HIF”
ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, background): “Under hypoxic conditions, HIF-1 activates the transcription of the genes encoding LDHA (298) and PDH kinase 1 (PDK1) (156, 249), which phosphorylates the catalytic subunit of PDH and inactivates it.”
Tumor cell metabolism: cancer's Achilles' heel. (2008, background): “Akt induces the translocation of HK to the outer mitochondrial membrane where it binds to VDAC, presumably because Akt interferes with the glycogen synthase kinase 3 (GSK3)-mediated phosphorylation of VDAC (Pastorino et al., 2005) or because Akt phosphorylates HK (Miyamoto et al.”
Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and its Potential for Therapeutic Intervention in Malignancy and Ischemia (2007, background): “In addition to increasing the expression of these enzymes, HIF-1 decreases mitochondrial oxygen consumption by activating pyruvate dehydrogenase kinase I and halting the citric acid cycle [17].”
Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. (2007, positive): “HFD, high-fat diet; CR, calorie restriction; BW, body weight; HIF-1 , hypoxia-inducible factor-1 ; GLUT1, glucose transporter 1; Hemox, heme oxygenase 1; PDK1, pyruvate dehydrogenase kinase 1.”
Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma (2019, background): “HIF1-signaling has been shown to decrease OXPHOS activity through multiple mechanisms (Hervouet et al., 2008; Papandreou et al., 2006).”
The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche (2010, background): “It regulates both glycolysis and mitochondrial respiration, inducing a metabolic shift toward anaerobic glycolysis (Hägg and Wennström, 2005; Kim et al., 2006b; Marı́n-Hernández et al., 2009; Maxwell et al., 2007; Papandreou et al., 2006; Wang et al., 1995; Zhang et al., 2007).”