Increased oxidative phosphorylation in response to acute and chronic DNA damage

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514997/pdf/npjamd201622.pdf

ARTICLE OPEN

Increased oxidative phosphorylation in response to

acute and chronic DNA damage

Lear E Brace1, Sarah C Vose2, Kristopher Stanya1, Rose M Gathungu3, Vasant R Marur3, Alban Longchamp1,
Humberto Treviño-Villarreal
1, Pedro Mejia1, Dorathy Vargas1, Karen Inouye1, Roderick T Bronson4, Chih-Hao Lee1, Edward Neilan5, Bruce S Kristal3 and James R Mitchell1

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/|Xpa/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.

npj Aging and Mechanisms of Disease (2016) 2, 16022; doi:10.1038/npjamd.2016.22; published online 13 October 2016

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