Are somatic mitochondrial DNA mutations relevant to our health? A challenge for mutation analysis techniques

A role of somatic mitochondrial (mt)DNA mutations in ageing and degenerative diseases was postulated decades ago, but this hypothesis remains untested. A substantial number of genetically engineered 'mutator' mouse lines with increased mtDNA mutation rates were expected to test the hypothesis. However, the results of mutator experiments are inconclusive and their interpretations are often contradictory. The authors argue that the problem, to a great extent, is the absence of a universally accepted accurate methodology of mtDNA mutational analysis and hence the lack of consensus with respect to the actual fractions of mtDNA mutations. Estimates by different existing methods vary by more than two orders of magnitude and the reason for this enormous discrepancy has yet to be fully accounted for. Furthermore, studies usually lack the vitally important details, such as the analysis of individual cells and multiple cell types, which is indispensable for rigorous evaluation of the impact of mtDNA mutations. New methods capable of accurate and detailed mutational analysis of mtDNA are in great need. A cell-by-cell mutational analysis may offer a solution.