PMID- 22544750 OWN - NLM STAT- MEDLINE DCOM- 20120920 LR - 20211021 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 287 IP - 26 DP - 2012 Jun 22 TI - Mitochondrial DNA variant for complex I reveals a role in diabetic cardiac remodeling. PG - 22174-82 LID - 10.1074/jbc.M111.327866 [doi] AB - 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. FAU - Sethumadhavan, Savitha AU - Sethumadhavan S AD - Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. FAU - Vasquez-Vivar, Jeannette AU - Vasquez-Vivar J FAU - Migrino, Raymond Q AU - Migrino RQ FAU - Harmann, Leanne AU - Harmann L FAU - Jacob, Howard J AU - Jacob HJ FAU - Lazar, Jozef AU - Lazar J LA - eng GR - P41 EB001980/EB/NIBIB NIH HHS/United States GR - R01 HL067244/HL/NHLBI NIH HHS/United States GR - HL-67244/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120427 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Biomarkers) RN - 0 (DNA, Mitochondrial) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 1.9.3.1 (Electron Transport Complex IV) RN - EC 7.1.1.2 (Electron Transport Complex I) SB - IM MH - Adenosine Triphosphate/metabolism MH - Animals MH - Biomarkers/metabolism MH - DNA, Mitochondrial/*genetics MH - Diabetes Complications/*metabolism MH - Disease Models, Animal MH - Echocardiography/methods MH - Electron Transport Complex I/*metabolism MH - Electron Transport Complex IV/metabolism MH - Genetic Variation MH - Glucose Tolerance Test MH - Heart Diseases/complications/*metabolism MH - Male MH - Microscopy, Electron, Transmission/methods MH - Mitochondria/metabolism MH - Mutation MH - Myocardium/pathology MH - Rats MH - Rats, Wistar PMC - PMC3381178 EDAT- 2012/05/01 06:00 MHDA- 2012/09/21 06:00 PMCR- 2013/06/22 CRDT- 2012/05/01 06:00 PHST- 2012/05/01 06:00 [entrez] PHST- 2012/05/01 06:00 [pubmed] PHST- 2012/09/21 06:00 [medline] PHST- 2013/06/22 00:00 [pmc-release] AID - S0021-9258(20)49746-7 [pii] AID - M111.327866 [pii] AID - 10.1074/jbc.M111.327866 [doi] PST - ppublish SO - J Biol Chem. 2012 Jun 22;287(26):22174-82. doi: 10.1074/jbc.M111.327866. Epub 2012 Apr 27.