The mitochondrial genome is David to the nuclear genome's Goliath. Mitochondrial DNA (mtDNA) encodes only 13 proteins, all of which are involved in energy metabolism vital for cell survival. Deletions of mtDNA have been reported in the substantia nigra, a region particularly affected by Parkinson disease. Bender et al. and Kraytsberg et al. now show extensive deletions of mtDNA in the substantia nigra in aged people and Parkinson disease patients in back-to-back studies in the May issue of Nature Genetics.
Bender et al. showed reduced cellular expression of cytochrome c oxidase (COX), an mtDNA-encoded enzyme, in midbrains from individuals with Parkinson disease. Unable to find explanatory point mutations in the mitochondrial genome, the authors of both papers assayed for mtDNA deletions, using laser-capture microdissection of substantia nigra cells and extended PCR to amplify almost the entire mitochondrial genome. Short products suggested mtDNA deletions in substantia nigra cells from both aged and Parkinsonian subjects. Products of different lengths were found in the cells examined, indicating that the somatic deletions were acquired in each cell independently. Bender et al. confirmed the presence of distinct deletions in different cells by cloning and sequencing the small PCR products. The authors noted cells with single small PCR products in both studies, suggesting clonal expansion, in which the deleted product was preferentially replicated in the cell.
To determine the prevalence of the mtDNA deletions, the authors used quantitative PCR comparing the expression of regions of the mitochondrial genome that often show mutations to the expression of regions that rarely show mutations. Kraytsberg et al. showed that the number of substantia nigra cells with mutations increased with age. In the aged individuals, the relative amount of deleted mtDNA per cell surpassed 60%, which is thought to be the threshold of mtDNA mutations required to precipitate phenotypic effects. Bender et al. provided a slightly lower estimate of deleted mtDNA per cell, calculating approximately 52% mtDNA deletion in subjects with Parkinson disease and 43% mtDNA deletion in aged controls. Both groups examined other regions of the brain, including the hippocampus, and found much lower rates of mtDNA deletions.
The authors then examined whether the mtDNA deletions might be responsible for decreased COX expression in the substantia nigra. Both groups showed that COX-deficient neurons had more mtDNA loss than COX-positivecells. The amount of deleted mtDNA in the COX-deficient cells exceeded the threshold of 60%.
These studies suggest that clonally expanded deletions of mtDNA might cause or contribute to neuronal loss in neurological disease and aging. Researchers do not know the mechanism of clonal expansion of mtDNA deletions or the reason for its specific prevalence in the substantia nigra. If Parkinson disease can be redefined as a susceptibility to mtDNA deletions, then its treatment and, more importantly, its prevention may be redefined as well.