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

Vasant R Marur,Roderick T Bronson,Alban Longchamp,Karen Inouye,Pedro Mejia,Chih-Hao Lee,Humberto Treviño-Villarreal,Bruce S Kristal,Lear E Brace,Dorathy Vargas,Sarah C Vose,James R Mitchell,Rose M Gathungu,Kristopher Stanya,Edward Neilan

doi:10.1038/npjamd.2016.22

Abstract

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.

Highlights

The process of generating energy through mitochondrial oxidative phosphorylation (OXPHOS) inevitably results in production of free radicals that can damage cellular macromolecules, including DNA
A number of cell types can rapidly shift between OXPHOS and glycolysis depending on environmental cues, e.g., upon antigen stimulation in the case of immune cells,[4] the potential of DNA damage to contribute to this process remains untested
Increased fatty acid oxidation (FAO)/OXPHOS is a cell-autonomous response to DNA damage Here, we identified a novel link between DNA damage and adaptive cellular/organismal energy metabolism involving an increase in FAO in particular and OXPHOS in general

Summary

Introduction

The process of generating energy through mitochondrial oxidative phosphorylation (OXPHOS) inevitably results in production of free radicals that can damage cellular macromolecules, including DNA. Consistent with this, interventions that increase OXPHOS (e.g., fasting) can lead to an increase in free radical generation, at least transiently.[1] Because of the potential detrimental effects of free radical damage, cells have evolved a variety of mechanisms of detoxification, many of which respond to oxidative stress in an inducible fashion. A number of cell types can rapidly shift between OXPHOS and glycolysis depending on environmental cues, e.g., upon antigen stimulation in the case of immune cells,[4] the potential of DNA damage to contribute to this process remains untested

Methods

Results

Conclusion