Oxidative damage to mitochondrial DNA and its relationship to ageing.

Mitochondria are the most important intracellular source of reactive oxygen species and are protected against them by enzymatic and nonenzymatic antioxidants. Nevertheless, mitochondrial DNA (mtDNA) is subject to severe oxidative damage, and much more so than nuclear DNA (nDNA). Damage is indicated by the detection of various base modifications, particularly 8-hydroxydeoxyguanosine (8OHdG), which can lead to point mutations because of mispairing. MtDNA is also fragmented to some extent. Conceivably, such fragmentation relates to the deletions found in mtDNA. Several hypotheses suggest that defective mitochondria contribute to, or are responsible for, ageing. Recent observations indicate that mitochondria in an old organism differ in many respects from those in a young organism. Thus, with ageing there is an increased production of reactive oxygen species, a decrease in certain antioxidants, a decreased transcription, translation, and cytochrome oxidase content, and an increase in the extent of DNA modifications. Major unresolved questions concerning the role of mtDNA changes in ageing are addressed: is there a causal relationship; what is the true extent of DNA damage; what are significance and functional consequences of mtDNA oxidation; are reactive oxygen species the cause of the DNA modifications found in vivo; what is the relationship between DNA damage and alterations of RNAs and proteins? Future studies promise to clarify the possible causal relationship between mitochondrial dysfunction, reactive oxygen species production, mtDNA modifications, and ageing.