Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway

Hypoxia induces the stabilization and transcriptional activation of the hyp oxia-inducible factor 1 alpha (HIF-1 alpha) protein, the regulatory member of the HIF-1 complex, The molecular mechanisms that are responsible for oxy gen sensing and the downstream pathways utilized by the hypoxic signal are still poorly understood, One hypothesis for oxygen sensing has postulated t hat reactive oxygen species generated at mitochondrial complex III are the initiators of the hypoxic signal. Here we find that mitochondrial DNA-less (rho degrees) cells have a normal response to hypoxia, measured at the leve l of HIF-1 alpha protein stabilization, nuclear translocation, and its tran scriptional activation activity. Furthermore, overexpression of catalase, e ither in the mitochondria or in the cytosol, fails to modify the hypoxia re sponse indicating that hydrogen peroxide is not a signaling molecule in the hypoxic signaling cascade that culminates with HIF-1 activation.