Effect of Aging and High Fat Diet on Mitochondrial and Cardiac Function in Mice with Altered Mitochondrial DNA Repair

Abstract

In the developing heart it is important that mitochondrial biogenesis is precisely coordinated with cardiac growth, because impaired bioenergetic function could lead to heart failure. Oxidative mitochondrial (mt) DNA damage and repair play critical roles in mitochondrial biogenesis during postnatal cardiac development in rodents; therefore heart development could be adversely impacted by alterations in mtDNA repair. Our previous results showed that young mice deficient in the DNA repair glycosylase Ogg1, the first enzyme in the base excision repair pathway in mitochondria, displayed increased mtDNA damage, altered mitochondrial respiration and left ventricle hypertrophy. Surprisingly, despite these abnormalities, cardiac function in 3 week old Ogg1‐deficient animals remained unchanged. However, whether these cardiac compensatory mechanisms remain effective during aging or under stress conditions is unclear. Here we test the hypothesis that increased oxidative stress associated with aging and obesity decreases cardiac function and leads to development of cardiomyopathy in mice with altered mitochondrial DNA repair. Fifteen month old mice of three genotypes ‐ wild type (WT), Ogg1 knock‐out (KO) animals and KO mice transgenically overexpressing mitochondria‐targeted Ogg1 (KOTG) were fed a high fat diet for 14 weeks and analyzed for mtDNA damage and copy number, mitochondrial respiration, and for cardiac function. Despite approximately equal weight gain in all three groups of animals, mitochondrial and cardiac function characteristics were different for these genotypes. Compared to WT, KO mice displayed increased oxidative mtDNA damage and decreased mtDNA copy number in cardiac tissue. Conversely, mtDNA oxidation was decreased and mtDNA copy number restored in KOTG mice. Echocardiographic analysis demonstrated increased left ventricle mass and decreased cardiac contractility in KO mice. Compared to hearts from WT mice, KO animals displayed a significant increase in mitochondrial oxygen flux at state III that remained elevated after adding an uncoupling agent. Taking into account decreases in respiratory ratio and abnormally low ATP levels in KO mice, these results indicate that there is constitutive uncoupling in the cardiac tissue of Ogg1 deficient animals. These changes in cardiac function and mitochondrial bioenergetics observed in KO mice were prevented in KOTG mice, which were not different from WT animals. In summary, oxidative stress associated with aging and obesity lead to elevated oxidative mtDNA damage, decreased mtDNA copy number, mitochondrial dysfunction, and impaired cardiac contractility in Ogg1 deficient mice. Restoration of mtDNA repair in KOTG animals eliminated these effects on mitochondrial and cardiac function, thus demonstrating an important role of mtDNA integrity in maintenance of mitochondrial and cardiac health. Further, these results suggest that abnormalities in mitochondrial and cardiac function can be manipulated by altering mtDNA damage and repair.Support or Funding InformationSupported by NIH.