Mitochondrial DNA Damage during Mitochondrial Lipid Peroxidation

Abstract

It is well known that the carcinogenic potency of radiation and chemical carcinogens is closely correlated with the induction of DNA damage (1–3); however, the ultimate mechanisms involved are far from clear. In the case of high energy radiation, generation of hydroxyl radicals (OH·) probably plays a key role, either by direct attack of OH· on DNA, or indirectly via initiation of lipid peroxidation (4,5). Initiation of lipid peroxidation may also be a consequence of the generation of oxygen centered radicals in the oxidative stress associated with metabolism of some chemical carcinogens(6). Thus lipid peroxidation may be one of the mechanisms linking both radiation and metabolism of chemical carcinogens to DNA damage. This view is supported by reports (7–12) that products of lipid peroxidation can cause DNA damage in model systems and mutations in prokaryotes. However, actual data showing DNA damage to eukaryotic genes by lipid peroxidation is limited and indirect (5,13). In this communication, evidence is reported showing extensive damage to DNA of liver mitochondria occurring concomitantly with mitochondrial lipid peroxidation. Mitochondrial rather than nuclear DNA was studied since the former exists as a discrete circular molecule of single molecular weight, which facilitates detection of small degrees of DNA damage. The study of the relationship between lipid peroxidation and DNA damage in mitochondria is important in the assessment of the carcinogenic potency of oxidative stress, especially since many strong carcinogenic agents preferentially attack mitochondrial DNA (14).