Increased oxidative phosphorylation in response to acute and chronic DNA damage

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.

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy

“…In work by Huang et al irinotecan treatment increased ROS generation in two human colorectal cancer cell lines, and this promoted apoptosis and reduced cell viability (29). Irinotecan elevated fatty acid oxidation (FAO) capacity in mouse tissues (liver and muscle) after treatment (30), and this effect was considered to be a common response to the increased energy demands when under genotoxic stress (because FAO provides reducing equivalents-NADH, FADH 2 , for efficient ATP generation via mitochondrial OXPHOS).…”

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

“…Through either direct interaction or via poly (ADP-ribose) (PAR) polymer formation PARP1 can modulate the activity of ataxia-telangiectasia mutated kinase (ATM) [23] and tumor suppressor protein 53 (p53) [24,25] involved in DNA damage response. Enhanced PARP1 activity also induces ATP depletion [26], which implies the activation of AMPK-activated protein kinase (AMPK) [27,28] that is responsible for the regulation of various cellular pathways including protein kinase B (AKT) and mammalian target of rapamycin (mTOR) [29][30][31]. This complex interplay between PARP1, ATM, AMKP, p53, AKT, and mTOR indicates that these DNA damage responders can fine-tune and modulate the interaction between DNA repair pathways with metabolism [32].…”

“…Studies using UVC irradiation revealed that UVC induced mitochondrial hyperfusion and resulted in enhanced ATP synthesis via oxidative phosphorylation (OXPHOS) [50]. Other authors demonstrated that UVC irradiation caused a significant increase in mitochondrial content, oxygen consumption, and fatty acid oxidation [28]. Nevertheless, the functional consequences of mitochondrial alterations after UVB-induced DNA damage and the molecular pathways leading to mitochondrial changes remain to be elucidated.…”

DNA damage response upon environmental contaminants: An exhausting work for genomic integrity

“…Otherwise, due to energy drop, it induces necrosis [3]. However, recent findings underline that an adaptive metabolism can occur, with a stimulation of AMPK (AMP-activated protein kinase), leading to an increase in fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) following DNA damage and PARP-1 activation [2] (Figure 1). …”

“…The impact of DNA damage and its impact on energy metabolism was firstly evidenced with the DNA damage sensor PARP-1 (poly(ADP-ribose) polymerase 1) [2]. Activated by numerous genotoxic stresses (by physical or chemical agents, upon acute or chronic exposure), PARP-1 triggers ATP and NAD + depletions, associated by mitochondrial depolarization, reactive oxygen species (ROS) production and apoptosis.…”