title: Mitochondrial DNA damage and repair during ischemia-reperfusion injury of the heart.
abstract: Ischemia-reperfusion (IR) injury of the heart generates reactive oxygen species that oxidize macromolecules including mitochondrial DNA (mtDNA). The 8-oxoguanine DNA glycosylase (OGG1) works synergistically with MutY DNA glycosylase (MYH) to maintain mtDNA integrity. Our objective was to study the functional outcome of lacking the repair enzymes OGG1 and MYH after myocardial IR and we hypothesized that OGG1 and MYH are important enzymes to preserve mtDNA and heart function after IR. Ex vivo global ischemia for 30min followed by 10min of reperfusion induced mtDNA damage that was removed within 60min of reperfusion in wild-type mice. After 60min of reperfusion the ogg1(-/-) mice demonstrated increased mtDNA copy number and decreased mtDNA damage removal suggesting that OGG1 is responsible for removal of IR-induced mtDNA damage and copy number regulation. mtDNA damage was not detected in the ogg1(-/-)/myh(-/-), inferring that adenine opposite 8-oxoguanine is an abundant mtDNA lesion upon IR. The level and integrity of mtDNA were restored in all genotypes after 35min of regional ischemia and six week reperfusion with no change in cardiac function. No consistent upregulation of other mitochondrial base excision repair enzymes in any of our knockout models was found. Thus repair of mtDNA oxidative base lesions may not be important for maintenance of cardiac function during IR injury in vivo. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease."
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Bliksøen
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Baysa
authors.affiliation: Department of Medical Biochemistry, University of Oslo, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Eide
authors.affiliation: Department of Microbiology, University of Oslo and Oslo University Hospital Rikshospitalet, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Department of Microbiology, University of Oslo and Oslo University Hospital Rikshospitalet, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Suganthan
authors.affiliation: Department of Emergency Medicine and Intensive Care, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Vaage
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, Norway; Center for Heart Failure Research, University of Oslo, Norway. Electronic address: k.o.stenslokken@medisin.uio.no.
authors.forename: K O
authors.initials: KO
authors.lastname: Stensløkken
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: G
authors.initials: G
authors.lastname: Valen
mesh_terms: D000818:Animals; D001835:Body Weight; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D018628:Gene Dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D013997:Time Factors
chemical_list: D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase
keywords: 8-Oxoguanine DNA glycosylase; DNA repair; Ischemia; Mitochondrial DNA