Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2012; 287(26):22174-82. DOI: 10.1074/jbc.M111.327866
Source: PubMed


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 T2DNmtFHH and T2DNmtWistar, 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 T2DNmtFHH and T2DNmtWistar 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 T2DNmtFHH 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 T2DNmtFHH, which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DNmtFHH 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.

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    • "MtDNA encodes seven subunits of respiratory chain, Complex I ND1 to ND6 and ND4L, cyt b (subunit of Complex III), three subunits of Complex IV, that is, cytochrome c oxidase, subunits 1, 2, 3, and ATP synthase subunits 6 and 8, plus 22 tRNAs and two ribosomal RNAs. Certain mtDNA mutations in these mt genes should lead to oxidative stress and initiate β cell dysfunction [184], such as in the heart [192]. Thus an ATP8 subunit mutation has been associated with increased mitochondrial superoxide generation, impaired GSIS, and increased β cell mass adaptation [179]. "
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