ABSTRACT
In recent years, inherited mutations in mitochondrial DNA (mtDNA) have been discovered to be associated with a variety of human diseases. mtDNA mutations can be thought of as forming a continuous spectrum from neutral (or even advantageous) polymorphisms through mildly or moderately deleterious changes to clearly pathological mutations, with devastating disease phenotypes. Supposedly neutral mtDNA polymorphisms, which have accumulated sequentially along radiating maternal lineages as the result of mtDNA evolution, define the mtDNA haplotypes of modern-day populations. In the recent years, haplogroup-defining polymorphisms have been suggested to contribute to the multifactorial aetiologies of many late-onset degenerative disorders by acting as “risk factors” that predispose individuals of certain mtDNA haplogroups to these diseases. Deleterious mtDNA mutations, on the other hand, have been found to be directly responsible for a wide range of phenotypes, most often by compromising the function of the mitochondrial oxidative phosphorylation (OXPHOS) system in individual cell types, tissues, or whole organisms. In addition to inherited mtDNA mutations, somatically acquired mutations and rearrangements have been shown to accumulate within many tissues during ageing. Such accumulation may lead to a progressive decline in energy production and the overall function of the tissue, thereby precipitating the onset of many agerelated degenerative diseases. Lastly, mtDNA mutations rarely act alone, and the clinical presentation of a mitochondrial disease is often the result of the interplay between the mitochondrial and the nuclear genomes as well as various environmental factors.
