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

A. Bartoletti-Stella, E. Mariani, I. Kurelac, A. Maresca, M. F. Caratozzolo, L. Iommarini, V. Carelli, L. H. Eusebi, A. Guido, G. Cenacchi, L. Fuccio, M. Rugolo, A. Tullo, A. M. Porcelli, G. Gasparre

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that γ-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 γ-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 1α (HIF1α) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1β inhibition by HIF1α, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1α stabilization, in fact, blunts the mitochondrial response to γ-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 HIF1α 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.

Original languageEnglish
Article numbere663
JournalCell Death and Disease
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • gamma rays
  • HIF1α
  • mitochondrial biogenesis
  • p53
  • senescence

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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