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

Abstract

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.

• Authors: Robert D Guzy, Beatrice Hoyos, Emmanuel Robin, Hong Chen, Liping Liu, Kyle D Mansfield, M Celeste Simon, Ulrich Hammerling, Paul T Schumacker
• Journal: Cell metabolism (Cell Metab) Vol. 1 Issue 6 Pg. 401-8 (Jun 2005) ISSN: 1550-4131 [Print] United States
• PMID: 16054089 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• Trans-Activators
• Transcription Factors
• endothelial PAS domain-containing protein 1
• Hydrogen Peroxide
• Electron Transport Complex III
• Oxygen

Topics

• Basic Helix-Loop-Helix Transcription Factors
• Cell Line, Tumor
• Electron Transport Complex III (metabolism)
• Humans
• Hydrogen Peroxide (metabolism)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mitochondria (enzymology, metabolism)
• Oxygen (metabolism)
• Reactive Oxygen Species (metabolism)
• Trans-Activators (metabolism)
• Transcription Factors (metabolism)