Abstract 16301: Oxidative Mitochondrial DNA Damage Affects Mitochondrial Respiration and Cardiac Development in Mice With Altered DNA Repair

Abstract

Impaired mitochondrial proliferation and function may lead to heart failure. Mitochondrial biogenesis during postnatal cardiac development in rodents is accompanied by oxidative mitochondrial (mt) DNA damage and repair. How mtDNA damage is linked to mitochondrial biogenesis is unknown, but our previous data suggest that site-specific mtDNA oxidation is involved in regulation of mtDNA replication. Here we tested the hypothesis that modulation of Ogg1, a DNA glycosylase mediating the first step in the base excision repair of oxidative mtDNA damage, coordinately affects mitochondrial function and cardiac development. Wild type (WT) mice, Ogg1 knock-out (KO) mice and KO mice transgenically overexpressing mitochondria-targeted Ogg1 (KOTG) were analyzed for mtDNA damage and replication using Southern and slot-blot analyses; mitochondrial respiration using oxygraph; and cardiac function using echocardiography. Compared to WT, KO mice showed increased oxidative mtDNA damage in cardiac tissue, (0.18 ± 0.04 vs. 0.35 ± 0.04 lesions/104 bp respectively, p<0.05), 2-fold decrease in mtDNA copy number (p<0.05) and increased heart:body mass ratio (4.96 ± 0.11 vs. 5.70 ± 0.10 mg/g respectively, p<0.05). Conversely, KOTG mice showed decreased mtDNA oxidation, restored mtDNA copy number and blunted elevation in cardiac mass. Echocardiography confirmed increased cardiac mass in KO mice with a trend towards decrease of cardiac contractility. Compared to hearts from WT mice, KO animals displayed significant increase in mitochondrial oxygen flux at state III (54.0 ± 8.1 vs. 93.9 ± 9.2 pmol/sec/ml/10 mg respectively, p<0.05) with concurrent decrease in respiratory ratio (2.56 ± 0.42 vs. 1.46 ± 0.27 respectively), indicating constitutive uncoupling in the cardiac tissue. Mitochondrial bioenergetics of KOTG mice did not differ from WT animals. In summary, Ogg1 deficiency in mice leads to elevated oxidative mtDNA damage; decreased mtDNA copy number and respiration; and cardiac hypertrophy. Restored mtDNA repair completely eliminated these effects on mitochondrial function and cardiac development. These results suggest that abnormalities in mitochondrial function and cardiac development can be manipulated by altering mtDNA damage and repair.