Mitochondrial respiration protects against oxygen-associated DNA damage

Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nature Communications (Impact Factor: 11.47). 04/2010; 1(1):5. DOI: 10.1038/ncomms1003
Source: PubMed


Oxygen is not only required for oxidative phosphorylation but also serves as the essential substrate for the formation of reactive oxygen species (ROS), which is implicated in ageing and tumorigenesis. Although the mitochondrion is known for its bioenergetic function, the symbiotic theory originally proposed that it provided protection against the toxicity of increasing oxygen in the primordial atmosphere. Using human cells lacking Synthesis of Cytochrome c Oxidase 2 (SCO2-/-), we have tested the oxygen toxicity hypothesis. These cells are oxidative phosphorylation defective and glycolysis dependent; they exhibit increased viability under hypoxia and feature an inverted growth response to oxygen compared with wild-type cells. SCO2-/- cells have increased intracellular oxygen and nicotinamide adenine dinucleotide (NADH) levels, which result in increased ROS and oxidative DNA damage. Using this isogenic cell line, we have revealed the genotoxicity of ambient oxygen. Our study highlights the importance of mitochondrial respiration both for bioenergetic benefits and for maintaining genomic stability in an oxygen-rich environment.

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    • "The ATM gene is a critical mediator in the response to DNA damage and was also found to stabilize mitochondrial DNA by regulating ribonucleotide reductases. These observations reveal the important role of ROS in tumorigenesis and suggest that optimization of the mitochondrial function (e.g. by redox metabolism and maintaining intracellular oxygen homeostasis) may have a protective role against oxidative damage of genomic DNA (Sung et al. 2010; Goh et al. 2011). Sablina et al. (2005) reported that low concentrations of p53 favor the expression of antioxidant genes under conditions of low cell stress, whereas p53 shows oxidant function to favor the expression of genes that promote both an increase in ROS and induction to apoptosis (Sablina et al. 2005). "
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    • "In contrast, for SCO2−/− cells iO2 profiles were similar to those in WT cells treated with AA, regardless of the presence of Baf (Figure 1A). This result was expected, since SCO2−/− cells deficient in the mitochondrial Complex IV [41] exhibit glycolytic type ATP production, low OCR (O2 consumption rate) and high iO2 levels [45]. "
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    • "In contrast, increased oxygen exposure may stabilize p53 through multiple mechanisms and promote mitochondrial biogenesis. Among the possible scenarios, molecular oxygen could regulate p53 via redox-sensitive proteins as discussed in the next section or it could serve as a substrate to increase ROS levels, which damage DNA, or activate signaling enzymes such as polo-like kinase 3 (PLK3) with resultant N-terminal phosphorylation and stabilization of p53 (Fig. 2) [18] [39]. As evidence of interaction between these two oxygen-sensitive transcription factors, p53 has been shown to decrease HIF-1a level by inhibiting its translation through p53-induced microRNA-107 or by promoting its degradation by MDM2-mediated ubiquitination [40] [41]. "
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