Recent years have seen the emergence of circumstantial evidence for a contribution of sequence variation in the mitochondrial genome to the risk for several metabolic disorders, including type 2 diabetes. A new study provides the first direct evidence that links mitochondrial genomic variation to inherited variation in the risk for type 2 diabetes in rats.

Proving a direct link between mitochondrial sequence variation and disease is not easy. For example, although maternal inheritance might be suggestive, other phenomena such as maternal environmental effects or imprinting can have the same effect. And separating the effects of mitochondrial and nuclear sequence variation has not been easy either. But this is exactly what Pravenec et al. achieved. As a result of several rounds of backcrossing of highly inbred spontaneously hypertensive rats with another highly inbred strain, the Brown Norway rat, the authors created conplastic strains that had two different mitochondrial genomes on a virtually identical nuclear genetic background. The spontaneously hypertensive rat strains were chosen because, in the past, this genetic background proved useful for detecting the effects of DNA variants on glucose and lipid metabolism.

Careful measurements of glucose and insulin levels, skeletal muscle glycogen content and ATP levels revealed significant differences between these strains. Sequence analysis of the two mitochondrial genomes identified a number of polymorphisms, including coding SNPs in several genes that encode proteins involved in important mitochondrial functions, such as oxidative phosphorylation. Comparing the coding SNPs with the corresponding residues in several vertebrate mitochondrial genomes revealed that they are relatively highly conserved; analysis of mitochondrial enzyme activities in these strains confirmed their functional significance. Although the relative contributions of each of the mitochondrial DNA (mtDNA) variants on glucose metabolism remains to be determined, these results provide a number of plausible links between mtDNA variation and functional differences that might underlie the condition.

Not only does this work demonstrate that naturally occurring variation in mitochondrial genomic sequence can ultimately lead to pathogenesis underlying common diseases, it also establishes an important animal model for studying the contribution of mtDNA variation to glucose metabolism.