ATP synthase is a key enzyme of mitochondrial energy conversion. In mammals, it produces most of cellular ATP. Alteration of ATP synthase biogenesis may cause two types of isolated defects: qualitative when the enzyme is structurally modified and does not function properly, and quantitative when it is present in insufficient amounts. In both cases the cellular energy provision is impaired, and diminished use of mitochondrial DeltamuH+ promotes ROS production by the mitochondrial respiratory chain. The primary genetic defects have so far been localized in mtDNA ATP6 gene and nuclear ATP12 gene, however, involvement of other nuclear genes is highly probable.

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....

A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in von Hippel-Lindau (vhl) gene. In the absence of functional pVHL, hypoxia-inducible factor (HIF) 1-alpha and HIF2-alpha subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and reactive oxygen species (ROS) metabolism. Transfection of these cells with vhl is known to restore HIF-alpha subunit degradation and to reduce glycolytic genes transcription. We show that such transfection with vhl of 786-0 CCRC (which are devoid of HIF1-alpha) also increased the content of respiratory chain subunits. However, the levels of most transcripts encoding OXPHOS subunits were not modified. Inhibition of HIF2-alpha synthesis by RNA interference in pVHL-deficient 786-0 CCRC also restored respiratory chain subunit content and clearly demonstrated a key role of HIF in OXPHOS regulation. In agreement with these observations, stabilization of HIF-alpha subunit by CoCl(2) decreased respiratory chain subunit levels in CCRC cells expressing pVHL. In addition, HIF stimulated ROS production and mitochondrial manganese superoxide dismutase content. OXPHOS subunit content was also decreased by added H(2)O(2.) Interestingly, desferrioxamine (DFO) that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl(2) significantly stimulates ROS production, DFO is known to prevent hydroxyl radical production by inhibiting Fenton reactions. This indicates that the HIF-induced decrease in OXPHOS is at least in part mediated by hydroxyl radical production.