Journal
CELL DEATH & DISEASE
Volume 4, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/cddis.2013.187
Keywords
gamma rays; mitochondrial biogenesis; p53; HIF1 alpha; senescence
Categories
Funding
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG8810]
- Italian Ministry of University (MIUR) grant [PRIN2008]
- Futuro in Ricerca 'TRANSMIT'
- DISCO TRIP - Fondazione Umberto Veronesi
- triennial AIRC fellowship 'Borromeo'
- Fondazione Umberto Veronesi
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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.
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