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 journalArticle

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

Fingerprint

Hypoxia-Inducible Factor 1
Gamma Rays
Organelle Biogenesis
Cell Aging
Radiotherapy
PPAR gamma
Mitochondrial DNA
Organelles
DNA Damage
Homeostasis
Neoplasms
Therapeutics

Keywords

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

ASJC Scopus subject areas

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

Cite this

Bartoletti-Stella, A., Mariani, E., Kurelac, I., Maresca, A., Caratozzolo, M. F., Iommarini, L., ... Gasparre, G. (2013). Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. Cell Death and Disease, 4(6), [e663]. https://doi.org/10.1038/cddis.2013.187

Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. / Bartoletti-Stella, A.; Mariani, E.; Kurelac, I.; Maresca, A.; Caratozzolo, M. F.; Iommarini, L.; Carelli, V.; Eusebi, L. H.; Guido, A.; Cenacchi, G.; Fuccio, L.; Rugolo, M.; Tullo, A.; Porcelli, A. M.; Gasparre, G.

In: Cell Death and Disease, Vol. 4, No. 6, e663, 06.2013.

Research output: Contribution to journalArticle

Bartoletti-Stella, A, Mariani, E, Kurelac, I, Maresca, A, Caratozzolo, MF, Iommarini, L, Carelli, V, Eusebi, LH, Guido, A, Cenacchi, G, Fuccio, L, Rugolo, M, Tullo, A, Porcelli, AM & Gasparre, G 2013, 'Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α', Cell Death and Disease, vol. 4, no. 6, e663. https://doi.org/10.1038/cddis.2013.187
Bartoletti-Stella A, Mariani E, Kurelac I, Maresca A, Caratozzolo MF, Iommarini L et al. Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. Cell Death and Disease. 2013 Jun;4(6). e663. https://doi.org/10.1038/cddis.2013.187
Bartoletti-Stella, A. ; Mariani, E. ; Kurelac, I. ; Maresca, A. ; Caratozzolo, M. F. ; Iommarini, L. ; Carelli, V. ; Eusebi, L. H. ; Guido, A. ; Cenacchi, G. ; Fuccio, L. ; Rugolo, M. ; Tullo, A. ; Porcelli, A. M. ; Gasparre, G. / Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α. In: Cell Death and Disease. 2013 ; Vol. 4, No. 6.
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