Increased oxidative phosphorylation in response to acute and chronic DNA damage.

Détails

ID Serval
serval:BIB_8E96BA1DCC9D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Increased oxidative phosphorylation in response to acute and chronic DNA damage.
Périodique
NPJ aging and mechanisms of disease
Auteur(s)
Brace L.E., Vose S.C., Stanya K., Gathungu R.M., Marur V.R., Longchamp A., Treviño-Villarreal H., Mejia P., Vargas D., Inouye K., Bronson R.T., Lee C.H., Neilan E., Kristal B.S., Mitchell J.R.
ISSN
2056-3973 (Print)
ISSN-L
2056-3973
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
2
Pages
16022
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa <sup>
-/-
</sup> |Xpa <sup>
-/-
</sup> mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes.
Pubmed
Web of science
Open Access
Oui
Financement(s)
Fonds national suisse / Carrières / P1LAP3_158895
Création de la notice
07/03/2021 13:53
Dernière modification de la notice
08/03/2021 7:26
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