The earth has been anaerobic and hypoxic for much of its 4.5 billion-year history. The relatively late rise in ambient oxygen likely required organisms to evolutionarily adapt to life in an oxygen-rich, oxidative environment1
. The symbiotic theory of the origin of the modern-day mitochondrion holds that the engulfment of aerobic proteobacteria by primordial anaerobic eukaryotes may have provided protection against oxygen toxicity2
. Although the mitochondrion has been extensively studied from the perspective of energy homeostasis, the originally proposed protective role against oxygen toxicity has received less attention. Recent studies suggest that improving mitochondrial function reduces the deleterious effects of oxidative stress such as ageing, cancer, metabolic and neurodegenerative diseases3–7
. The concordance of these observations across species from yeast to mammal indicates that other effects of mitochondrial respiration beyond bioenergetic function may be important for aerobic life.
Tumorigenesis is thought to be driven by the multistep acquisition of mutations caused by genotoxic stresses, such as DNA damaging agents and reactive oxygen species (ROS). Among the many transcriptional targets of the tumour suppressor gene p53
are anti-oxidant enzymes and the RRM2B
gene encoding the regulatory subunit of ribonucleotide reductase, which prevents mitochondrial DNA depletion and dysfunction8–10
. The tumour suppressor encoded by the ATM
gene, a critical mediator of DNA damage responses, has also been shown to stabilize mitochondrial DNA through regulation of ribonucleotide reductases in a tissue-specific manner11
. These observations implicate ROS in tumorigenesis and suggest that the optimization of mitochondrial function, possibly through redox and maintenance of intracellular oxygen homeostasis, has a protective role against oxidative damage to genomic DNA.
In bacteria, physiological levels of oxygen have been shown to be mutagenic12
. Whether the reduction of oxygen by respiration in human cells protects against DNA damage-induced growth arrest or tumour-promoting mutations remains to be genetically demonstrated. Although many studies have linked oxidative stress and cancer, clinical investigations have not uniformly demonstrated a benefit of antioxidants against cancer, and the use of these drugs as chemopreventives remains controversial13–16
. Such disparate observations indicate a need to better understand the cellular control of oxygen use and the relationship between oxidative stress and tumorigenesis.
We recently reported the regulation of mitochondrial respiration by p53 through its transcriptional target gene Synthesis of Cytochrome c Oxidase 2
. The SCO2 protein is essential for the assembly of the mitochondrial cytochrome c
oxidase (COX) complex (IV), the metabolic centre of eukaryotic oxygen consumption18,19
. Although the biological significance of the p53/SCO2 pathway remains to be clarified, the major role of p53 as ‘guardian of the genome’20,21
would suggest that the regulation of respiration may confer genomic protection. We tested this hypothesis by genetically disrupting SCO2
, thereby eliminating mitochondrial respiration, in a human cell line. Indeed, loss of respiration disrupts redox home-ostasis and increases the intracellular oxygen availability that contributes to increased ROS formation and oxidative DNA damage. Thus, our genetic study demonstrates the importance of optimizing mitochondrial function, which when dysfunctional has been proposed to lie at the core of degenerative diseases related to ageing and cancer22