The mitochondrial genome, aging and neurodegenerative disorders.

Mitochondria contain the only extra-nuclear source of DNA. Under evolutionary pressure mitochondrial DNA (mtDNA) has adapted from genomes containing over 1,000 kb containing significant quantities of non-coding DNA to the highly compact mammalian mtDNA. In humans, the mitochondrial genome consists of a small (16.5 kb) double-stranded circular genome constituting less than 1% of the total cellular nucleic acid, yet its role is essential for the survival and function of the mitochondria and hence the cell (Fig. 1). Human mtDNA is a highly efficient structure in terms of expressed DNA containing no introns. It encodes for 37 genes, all of which are involved in synthesising subunits of the respiratory chain complex, either directly as 13 essential polypeptide components, or indirectly as the 22 transfer RNAs and the 2 ribosomal RNAs of the mitochondrial protein synthesis machinery (Fig. 1b). Human cells contain several hundred to many thousand mitochondria, with each mitochondrion having 2–10 copies of mtDNA [1]. Therefore several thousand copies of mtDNA can be present within a single cell. Both mutated and wild-type (normal) mtDNA can co-exist in any proportion, a situation termed heteroplasmy. The level of mutant mtDNA can vary considerably between mitochondria, cells and even tissues within the same individual. The mitochondrial genome mutates at a faster rate than its nuclear counterpart for several reasons. Firstly mitochondria lack nucleotide excision and recombination DNA repair mechanisms [2]. Secondly mtDNA lacks the structurally DNA stabilising proteins known as histones. Thirdly mtDNAs reside and replicate close to the inner mitochondrial membrane and hence are exposed