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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Available from: Wenzhe Ma, Oct 01, 2015
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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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    ABSTRACT: Researchers have recently shown an increased interest in free radicals and their role in the tumor microenvironment. Free radicals are molecules with high instability and reactivity due to the presence of an odd number of electrons in the outermost orbit of their atoms. Free radicals include reactive oxygen and nitrogen species, which are key players in the initiation and progression of tumor cells and enhance their metastatic potential. In fact, they are now considered a hallmark of cancer. However, both reactive species may contribute to improve the outcomes of radiotherapy in cancer patients. Besides, high levels of reactive oxygen species may be indicators of genotoxic damage in non-irradiated normal tissues. The purpose of this article is to review recent research on free radicals and carcinogenesis in order to understand the pathways that contribute to tumor malignancy. This review outlines the involvement of free radicals in relevant cellular events, including their effects on genetic instability through (growth factors and tumor suppressor genes, their enhancement of mitogenic signals, and their participation in cell remodeling, proliferation, senescence, apoptosis, and autophagy processes; the possible relationship between free radicals and inflammation is also explored. This knowledge is crucial for evaluating the relevance of free radicals as therapeutic targets in cancer.
    SpringerPlus 08/2013; 2(1):404. DOI:10.1186/2193-1801-2-404
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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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    ABSTRACT: Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide bafilomycin A1 (Baf) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in intracellular O2 (iO2) to 0-10 microM, induced by Baf is sufficient for stabilization of hypoxia inducible factors HIF-1alpha and HIF-1alpha, coupled with an increased expression of target genes including glucose transporter 1 (GLUT1), HIF prolyl hydroxylase domain 2 (PHD2) and carbonic anhydrase IX (CAIX). Under the same hypoxic conditions, treatment with Baf causes neither decrease in iO2 nor HIF-alpha stabilization in the low-respiring HCT116 cells deficient in cytochrome c oxidase. Both cell types display equal capacities for HIF-alpha stabilization by hypoxia mimetics DMOG and CoCl2, thus suggesting that the effect of Baf under hypoxia is driven mainly by mitochondrial respiration. Altogether, by activating HIF signalling under moderate hypoxia, mitochondrial uncoupling can play important regulatory role in colon cancer metabolism and modulate adaptation of cancer cells to natural hypoxic environments.
    Bioscience Reports 09/2012; 32(Pt 6). DOI:10.1042/BSR20120085 · 2.64 Impact Factor
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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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    ABSTRACT: The genetic links between p53 and metabolic processes such as oxidative phosphorylation are being studied with increasing interest given that cellular metabolism seems to play an important role in tumorigenesis. This review focuses on how p53 regulation of various metabolic genes may influence redox homeostasis, as the genome is constantly susceptible to oxidative damage, a consequence of living in an aerobic environment. Because p53-like genetic sequences are also found in life forms that may not necessarily benefit from tumor suppression, an evolutionary introduction is given in an attempt to understand why p53 might regulate a basic cellular activity such as metabolism. The presented epidemiologic and experimental data suggest that one reason may be for the homeostatic regulation of oxygen, the essential substrate for reactive oxygen species generation.
    Free Radical Biology and Medicine 07/2012; 53(6):1279-85. DOI:10.1016/j.freeradbiomed.2012.07.026 · 5.74 Impact Factor
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