Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.
Mammalian cells detect decreases in oxygen concentrations to activate a variety of responses that help cells adapt to low oxygen levels (hypoxia). One such response is stabilization of the protein HIF-1 alpha, a component of the transcription factor HIF-1. Here we show that a small interfering RNA (siRNA) against the Rieske iron-sulfur protein of mitochondrial complex III prevents the hypoxic stabilization of HIF-1 alpha protein. Fibroblasts from a patient with Leigh's syndrome, which display residual levels of electron transport activity and are incompetent in oxidative phosphorylation, stabilize HIF-1 alpha during hypoxia. The expression of glutathione peroxidase or catalase, but not superoxide dismutase 1 or 2, prevents the hypoxic stabilization of HIF-1 alpha. These findings provide genetic evidence that oxygen sensing is dependent on mitochondrial-generated reactive oxygen species (ROS) but independent of oxidative phosphorylation.
Brunelle
Joslyn K
JK
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Bell
Eric L
EL
Quesada
Nancy M
NM
Vercauteren
Kristel
K
Tiranti
Valeria
V
Zeviani
Massimo
M
Scarpulla
Richard C
RC
Chandel
Navdeep S
NS
D014450:Electron Transport Complex III / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D014450:Electron Transport Complex III; D010100:Oxygen