Faculty Collaboration Database

Mitochondrial DNA variant for complex I reveals a role in diabetic cardiac remodeling. J Biol Chem 2012 Jun 22;287(26):22174-82

Date

05/01/2012

Pubmed ID

22544750

Pubmed Central ID

PMC3381178

DOI

10.1074/jbc.M111.327866

Scopus ID

2-s2.0-84862699122 (requires institutional sign-in at Scopus site)   21 Citations

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.

Author List

Sethumadhavan S, Vasquez-Vivar J, Migrino RQ, Harmann L, Jacob HJ, Lazar J

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Biomarkers
DNA, Mitochondrial
Diabetes Complications
Disease Models, Animal
Echocardiography
Electron Transport Complex I
Electron Transport Complex IV
Genetic Variation
Glucose Tolerance Test
Heart Diseases
Male
Microscopy, Electron, Transmission
Mitochondria
Mutation
Myocardium
Rats
Rats, Wistar