Increased oxidative phosphorylation in response to acute and chronic DNA damage

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. A link between DNA damage and cellular metabolism could benefit patients with premature aging disorders and lead to safer cancer treatments. Cells consume considerable energy to repair the destructive effects of chemicals, radiation and aging on the chromosomes. Researchers led by James Mitchell of the Harvard T.H. Chan School of Public Health have found that the damage-induced activation of these pathways accelerates fat metabolism and boosts production of ATP, the cell’s energetic currency. This metabolic shift is beneficial for cellular health, and appears to be an important defense mechanism in premature aging disorders like Cockayne syndrome. The researchers hypothesize that interventions such as dietary restriction could help protect against the side effects of DNA damage from radio- or chemotherapy by switching cellular energy metabolism into a more efficient state.