Postnatal cardiac development in transgenic mice with altered expression of the DNA glycosylase Ogg1 (573.4)

Abstract

A switch from cardiomyocyte hyperplasia to hypertrophy underlies postnatal cardiac development in rodents. Interestingly, this transition is associated with robust mitochondrial biogenesis, which, paradoxically, is accompanied by oxidative mitochondrial (mt) DNA damage and repair (Pohjoismaki et al, NAR, 2012). Whether mtDNA damage and repair are functionally linked to mitochondrial biogenesis is unknown, but previous experiments showed that controlled DNA damage and repair are important for transcription of nuclear genes (Al‐Mehdi et al, Sci Signaling, 2012). To determine if a similar mechanism could be operative in the mitochondrial genome during postnatal cardiac development, we measured oxidative damage in the mtDNA D‐loop transcriptional regulatory sequence and the coding region as a function of time in hearts derived from wild type (WT) mice, knock‐out mice deficient in the DNA glycosylase Ogg1 (KO), and in KO mice transgenically over‐expressing human OGG1 targeted to mitochondria. In comparison to WT animals, KO mice displayed higher mtDNA damage which preceded an exaggerated postnatal increase in heart‐to‐body mass ratio. Conversely, KO mice over‐expressing mitochondria‐targeted OGG1 displayed decreased mtDNA oxidation and a blunted elevation in cardiac mass relative to KO mice. These results suggest mtDNA damage and repair may be functionally linked to postnatal cardiac development.Grant Funding Source: Supported by the NIH R21HL102789, R01HL113614