title: Mitochondrial DNA variant for complex I reveals a role in diabetic cardiac remodeling.
abstract: Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN(mtFHH) and T2DN(mtWistar), where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN(mtFHH) and T2DN(mtWistar) showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN(mtFHH) showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN(mtFHH), which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN(mtFHH) were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Savitha
authors.initials: S
authors.lastname: Sethumadhavan
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vasquez-Vivar
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.forename: Leanne
authors.initials: L
authors.lastname: Harmann
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D048909:Diabetes Complications / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D042967:Electron Transport Complex I / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006331:Heart Diseases / Q000150:complications / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I