Abstract 1707: Mitochondrial DNA (mtDNA) mutations in the left ventricle of Goto-Kakizaki diabetic rats.
Diabetic cardiomyopathy is associated with significant increases in apoptosis and loss of cardiac mass. Mitochondrial dysfunction has a significant role in the development and complications of diabetic cardiomyopathy. Although the mitochondria have developed defense mechanisms to handle ROS, diabetes-induced hyperglycemia greatly increases oxidative stress and accelerates the rate of damage. However, less clear are the mechanisms that lead to failure, since short-term hyperglycemia activates antioxidative defenses. This suggests that there may be limits to adaptability or that the chronic hyperglycemia ultimately produces an accumulation of errors with which the mitochondria are unable to cope. The GK rat is a nonobese model of type 2 diabetes that develops significant hyperglycemia, hyperinsulinemia, and glucose intolerance at an early age. Long range PCR demonstrated the presence of deletions in 9 month-old GK LV but not 3 month old GK or Wistar LV of either age. Using the temporal temperature gradient electrophoresis (TTGE) method to analyze LV mtDNA mutations, we observed a number of basepair substitutions or insertions in the 3′ end of COX3 from GK LV, but not from Wistar, and the frequency of these errors increased with age. TTGE analysis of the D Loop region also found the presence of mtDNA mutations. Analysis of LV mitochondrial function demonstrated a significant reduction in LV cytochrome oxidase activity (Wistar; 0.16± 0.02, GK; 0.10± 0.01 nmole/min/mg protein) and this was accompanied by a significant decrease (40%) in mitochondrial copy number. The accumulation of mtDNA mutations and concomitant mitochondrial dysfunction may be the underlying pathology for many complications of diabetes, including vascular dysfunction, renal failure, and congestive heart failure.