Rationale: Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. Objective: The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity. Methods and Results: Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis.As p53 Key Words: aerobic Ⅲ exercise Ⅲ mitochondrial DNA Ⅲ p53 Ⅲ TFAM A cross populations aerobic exercise capacity inversely correlates with cardiovascular disease and all-cause mortality. 1-3 Our report of a marked reduction in the maximal exercise capacity of p53 homozygous knockout (p53 Ϫ/Ϫ ) mice and subsequent confirmation by others provided physiological evidence for p53 as an important mediator of aerobic metabolism. 4,5 We previously showed that p53 promotes mitochondrial respiration in human and murine cells by regulating the transcription of Synthesis of Cytochrome c Oxidase 2 (SCO2), a gene essential for oxidative phosphorylation. 4,6 A concurrent report demonstrating that p53 directly suppresses glycolysis through TIGAR, a p53-dependent regulator of glycolysis and apoptosis, suggested that p53 can coordinate aerobic and glycolytic metabolism. 7 Multiple factors contribute to aerobic exercise capacity, but one major determinant is the mitochondrial content of skeletal muscle as demonstrated by a genetic selection experiment. 8 A recent study showed decreased mitochondrial density in the skeletal muscle of p53-deficient mice, 5 but the genetic mechanism orchestrating this change has remained unclear. A number of other studies have also associated p53 with exercise response and mitochondrial function. For example, p53 levels are increased after acute exercise, and the transition from glycolysis to oxidative metabolism during development is dependent on p53. 9,10 p53 can transactivate ribonucleotide reductase p53R2 (RRM2B) which is important for maintaining mtDNA in skeletal muscle. 11 Additionally, 2 recent studies have shown asso-

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.

The genetic basis of increased glycolytic activity observed in cancer cells is likely to be the result of complex interactions of multiple regulatory pathways. Here we review the recent evidence of a simple genetic mechanism by which tumor suppressor p53 regulates mitochondrial respiration with secondary changes in glycolysis that are reminiscent of the Warburg effect. The biological significance of this regulation of the two major pathways of energy generation by p53 remains to be seen.