Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.
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.
Guzy
Robert D
RD
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Hoyos
Beatrice
B
Robin
Emmanuel
E
Chen
Hong
H
Liu
Liping
L
Mansfield
Kyle D
KD
Simon
M Celeste
MC
Hammerling
Ulrich
U
Schumacker
Paul T
PT
D051792:Basic Helix-Loop-Helix Proteins; D045744:Cell Line, Tumor; D014450:Electron Transport Complex III / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014450:Electron Transport Complex III; D006861:Hydrogen Peroxide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human