Colorectal cancers have a lower mitochondrial DNA mutation frequency than normal tissue.

  • Major finding: Colorectal cancers have a lower mitochondrial DNA mutation frequency than normal tissue.

  • Concept: The shift from oxidative phosphorylation to glycolysis in tumors may protect mitochondrial DNA.

  • Impact: Induction of mitochondrial DNA damage may be an effective anticancer strategy.

Mitochondrial DNA mutations that confer a selective growth advantage have been identified in human tumors, but it is unknown if mitochondrial genomes are unstable in cancer. Ericson and colleagues determined the mitochondrial DNA mutation frequency in 21 colorectal cancers and adjacent nontumor tissue using the random mutation capture assay, a method that quantifies the number of substitutions at intragenic restriction enzyme sites. Surprisingly, the tumors had an average mutation rate that was approximately 3-fold lower than that of matched normal tissue and also lower than that of benign adenomas. The most common base substitution in the adenomas and matched normal tissues was cytosine:guanine to thymine:adenine, which occurs due to oxidative damage–induced deamination of cytosine bases. This mutation spectrum was significantly less common in tumors, which led the authors to posit that the shift from oxidative phosphorylation to anaerobic glycolysis that occurs in tumor cells reduces the production of reactive oxygen species in the mitochondria, which in turn leads to decreased mitochondrial DNA damage. Consistent with this hypothesis, a high ratio of lactate, the end product of glycolysis, to citrate, a tricarboxylic acid cycle intermediate that is a precursor to oxidative phosphorylation, was negatively correlated with mutation frequency. Although analyses of mitochondrial mutation rates are needed in additional cancers and the role of mitochondrial DNA repair should be explored, these findings provide initial evidence that a glycolytic shift might protect tumor cells from oxidative damage and contribute to cell immortality. Cancer cells may therefore be selectively sensitive to agents that directly induce mitochondrial DNA damage.

Ericson NG, Kulaweic M, Vermulst M, Sheahan K, O'Sullivan J, Salk JJ, et al. Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet 2012;6:e1002689.