Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains

Abstract

Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.[Supplemental material is available online at www.genome.org.]Recently, the potential role of the mitochondrial genome in the pathogenesis of type 2 diabetes and other common diseases has begun to attract increasing attention (Wallace 2005). Mitochondrial DNA is exclusively of maternal origin, and some studies have indicated that the inheritance of type 2 diabetes may be biased toward the maternal lineage (Alcolado et al. 2002). Sun et al. (2003) have estimated that mitochondrial DNA mutations might be involved in >20% of cases of type 2 diabetes. In addition, Wilson et al. (2004) have identified a homoplasmic mitochondrial DNA variant associated with the maternal transmission of hypercholesterolemia, hypomagnesemia, and hypertension through four generations of a large, carefully analyzed kindred. Rare forms of maternally transmitted diabetes associated with heteroplasmic mitochondrial DNA variants have also been reported (Mathews and Berdanier 1998;Maassen et al. 2005). These observations provide indirect evidence that sequence variation in the mitochondrial genome might contribute to inherited variation in the risk for type 2 diabetes and related metabolic disorders.Notwithstanding recent advances in mitochondrial genome research, multiple confounding factors have made it difficult to unequivocally establish a role for mitochondrial DNA variation in the regulation of risk factors for diabetes or other complex metabolic phenotypes. For example, effects of maternal environment or imprinting may contribute to matrilineal transmission patterns of the phenotypes of interest....

Family-based mitochondrial association study of traits related to type 2 diabetes and the metabolic syndrome in adolescents

“…Another limitation of mitochondrial association studies is that they are potentially confounded by the nuclear background as there is significant cross-talk between the two systems. Some of the most convincing evidence for a role of mtDNA in metabolic phenotypes comes from studies of mice with identical nuclear genomes, but different mitochondrial genomes [11]. In this regard, twin studies may prove to be a valuable resource in trying to uncover the role of mitochondria in disease.…”

“…Mitochondria may also play a role in the metabolic syndrome, as evidenced by a mutation in the tRNA ILE gene (also known as MT-TI) at nucleotide position 4,291 causing hypertension, hypercholesterolaemia and hypomagnesaemia [10]. A recent study using rats with identical nuclear genomes but differing mitochondria showed that mitochondrial variants have a direct effect on a number of metabolic phenotypes, including triacylglycerol levels [11].…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Moreover, while fibrogenesis/fibrinolysis genes are predicted to be strong candidates to influence liver fibrosis, only one report has shown a link between transforming growth factor-β 1 (TGF-β 1) and angiotensinogen polymorphisms and obesity induced liver fibrosis [141]. Lastly, it should be mentioned that an association between naturally occurring variations in the mitochondrial genome and conditions of the cardiometabolic syndrome has been proposed [142,143]. Recently, Pravenec et al [142] using conplastic rat strains with the same nuclear genome but dissimilar mitochondrial genomes encoding oxidative phosphorylation proteins of differing amino acid composition showed differences in glucose and glycogen metabolism; two risk factors for type 2 diabetes.…”

“…Lastly, it should be mentioned that an association between naturally occurring variations in the mitochondrial genome and conditions of the cardiometabolic syndrome has been proposed [142,143]. Recently, Pravenec et al [142] using conplastic rat strains with the same nuclear genome but dissimilar mitochondrial genomes encoding oxidative phosphorylation proteins of differing amino acid composition showed differences in glucose and glycogen metabolism; two risk factors for type 2 diabetes. Whether mtDNA variants are linked to risk factors associated with steatosis, hepatitis, and fibrosis/ cirrhosis is a stimulating concept and one that clearly requires further study.…”

Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue

“…The amount of mitochondrial DNA (mtDNA) was estimated as described earlier. 21 The results in pioglitazone treated rats were expressed as fold increases relative to the mean normalized expression level of the control rats that was arbitrarily defined as 1.…”