Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α

Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that gamma-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to gamma-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1 alpha (HIF1 alpha) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1 beta inhibition by HIF1 alpha, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1 alpha stabilization, in fact, blunts the mitochondrial response to gamma-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1 alpha increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence.