Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.

By R. Guzy, B. Hoyos, E. Robin, Hong Chen, Liping Liu, Kyle D Mansfield, M. C. Simon, Ulrich Hämmerling, P. Schumacker. Cell Metabolism, 2005

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Multicellular organisms initiate adaptive responses when oxygen (O(2)) availability decreases, but the underlying mechanism of O(2) sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1 alpha and HIF-2 alpha and that an increase in reactive oxygen species (ROS) links this complex to HIF-alpha stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 alpha stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol.

Subfields: Cancer Research, Ecology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9000534034443c3e94e03c2741e4f45d118fa4d2

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Citations in the corpus

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, positive): “ER stress mediated activation of central signaling hubs such as HIF1α, STAT3, NRF2 and NFκB facilitate cell survival under harsh microenvironmental conditions and preserve tumor initiating cell function.”
How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). (2010, background): “…signals from the mitochondrial compartment to other compartments of the cell (Barja, 1993; Rhee et al., 2003; Kaelin, 2005; Connor et al., 2005; Guzy et al., 2005; Guzy and Schumacker, 2006; Chandel and Budinger, 2007; Schulz et al., 2007; Veal et al., 2007; Owusu-Ansah et al., 2008; Finley…”
Oxidant Mechanisms in Renal Injury and Disease (2016, positive): “Moderately increased mitochondria ROS results in stabilization of hypoxia-inducible factor (HIF) in endothelial cells (99) and in stimulating nuclear factor-E2-related factor (NRF-2) (235), effects that are both protective against oxidative stress and renoprotective (107,196).”
Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. (2005, positive): “This, along with other emerging genetic models (Brunelle et al., 2005 [this issue of Cell Metabolism]; Guzy et al., 2005 [this issue of Cell Metabolism]), will provide valuable tools for investigating the role of the mitochondria in other hypoxic phenomena.”
Hydrogen peroxide sensing, signaling and regulation of transcription factors (2014, background): “Furthermore, the high levels of mitochondria-derived reactive oxygen species generated by hypoxia were considered to be essential for HIF-1α stabilization and this effect was reversed upon overexpression of either catalase or glutathione peroxidase 1 [134][234][235].”
Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia (2006, methodology): “The decrease in respiration during prolonged hypoxia, a response termed ‘hypoxic conformance of HIF-α HIF-β HIF-βHIF-α Transcription DNA Hypoxia PHD Fe O 2-oxoglutarate 2+ 2 HIF-α HO HIF-α HO Normoxia vHL U UU U Mitochondria ROS Anoxia TRASH FIH Cul2 EL B EL C RBX1 p300/CBP Figure 1.”
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. (2006, methodology): “This model is compatible with findings that hypoxia-induced mitochondrial ROS is necessary and sufficient for the stabilization of HIF-1 (Brunelle et al., 2005; Guzy et al., 2005; Kaelin, 2005), which would in turn activate PDK1 and thereby attenuate the persistence of potentially lethal ROS.”