Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1α during Hypoxia

By Navdeep S. Chandel, D. S. McClintock, C. Feliciano, T. Wood, J. Melendez, Ana M. Rodriguez, P. Schumacker. Journal of Biological Chemistry, 2000

1,495 citations recorded by the source corpus.

During hypoxia, hypoxia-inducible factor-1α (HIF-1α) is required for induction of a variety of genes including erythropoietin and vascular endothelial growth factor. Hypoxia increases mitochondrial reactive oxygen species (ROS) generation at Complex III, which causes accumulation of HIF-1α protein responsible for initiating expression of a luciferase reporter construct under the control of a hypoxic response element. This response is lost in cells depleted of mitochondrial DNA (ρ0 cells). Overexpression of catalase abolishes hypoxic response element-luciferase expression during hypoxia. Exogenous H2O2 stabilizes HIF-1α protein during normoxia and activates luciferase expression in wild-type and ρ0 cells. Isolated mitochondria increase ROS generation during hypoxia, as does the bacterium Paracoccus denitrificans. These findings reveal that mitochondria-derived ROS are both required and sufficient to initiate HIF-1α stabilization during hypoxia.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/032d6db639a43084d3aa110b2ecca3c74504aad3

How researchers see this paper

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In Cancer Research

1. G. Semenza
2. P. Schumacker
3. Craig B. Thompson
4. M. C. Simon
5. R. Guzy
6. Eyal Gottlieb
7. M. Murphy
8. Ian Tomlinson

In Genetics

1. P. Schumacker
2. M. C. Simon
3. G. Semenza
4. R. Guzy
5. Craig B. Thompson
6. K. Griendling
7. Kyle D Mansfield
8. C. V. Dang

In Molecular Biology

1. G. Semenza
2. P. Schumacker
3. Navdeep S. Chandel
4. Craig B. Thompson
5. M. C. Simon
6. M. Murphy
7. R. Guzy
8. Eyal Gottlieb

Citations in the corpus

• NRF2 and the Hallmarks of Cancer. (2018, background): “…and Schumacker, 2014, Cipolla and Lodhi, 2017), aberrant activation of receptors (Yuan et al., 2013, Huang et al., 2012) or prooxidant enzymes (Ogrunc et al., 2014, Kodama et al., 2013), hypoxia (Lluis et al., 2007, Chandel et al., 2000), and anchorage-independent growth (Jiang et al., 2016).”
• Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. (2005, neutral): “Increases in ROS generation during normoxia can also trigger hypoxic responses, including HIF-1α stabilization (BelAiba et al., 2004; Chandel et al., 2000; Goyal et al., 2004), suggesting that mtROS are sufficient to mimic hypoxia.”
• Hypoxia-induced metabolic and antioxidant enzymatic activities in the estuarine fish Leiostomus xanthurus (2002, background): “When oxygen concentrations decline to hypoxic levels, there is an increase in the production of ROS, despite the reduction in aerobic respiration (Filho, 1996; Chandel et al., 2000).”
• Regulation of reactive oxygen species generation in cell signaling (2011, background): “In early studies, it was suggested that mitochondrial production of ROS is involved in hypoxia signaling (Chandel et al., 1998; 2000).”