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Author Summary Mitochondria, the ‘power plant’ of the cell, have their own distinct genome (mtDNA), whose sequence varies among individuals around the globe. This variation, which was formed by the accumulation of mutations (variants) during the course of evolution, appears to alter the susceptibility to common complex diseases (such as Parkinson's disease and diabetes). However, since the accumulation of mtDNA mutations over time results in the formation of new combinations (genetic backgrounds), it is not clear which of the mutations are functional and which are “evolutionary silent hitchhikers”. Thus we aimed at assessing the functionality of mtDNA genetic variants, focusing on variants within the mtDNA regulatory region, hypothesizing that they could affect mtDNA activity and maintenance. We found that a variant defining mtDNA genetic background ‘J’ significantly increased the transcriptional efficiency and elevated mtDNA copy numbers in cells, as compared to other genetic backgrounds. Hence, mtDNA regulatory region variants can affect mtDNA maintenance, which may partially account for the involvement of this genetic background in disease susceptibility. Our analysis demonstrates, for the first time, the functional impact of a particular mtDNA variant that was fixed during evolution. Moreover, our findings underline the functionality of mtDNA variants in the evolutionary variable regulatory region.
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