title: Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions.
abstract: The mitochondrial DNA base modification 8-hydroxy 2'-deoxyguanine (8-OHdG) is one of the most common DNA lesions induced by reactive oxygen species (ROS) and is considered an index of DNA damage. High levels of mitochondrial 8-OHdG have been correlated with increased mutation, deletion, and loss of mitochondrial (mt) DNA, as well as apoptosis. 8-Oxoguanosine DNA glycosylase-1 (OGG1) recognizes and removes 8-OHdG to prevent further DNA damage. We evaluated the effects of OGG1 on mtDNA damage, mitochondrial function, and apoptotic events induced by oxidative stress using H9C2 cardiac cells treated with menadione and transduced with either Adv-Ogg1 or Adv-Control (empty vector). The levels of mtDNA 8-OHdG and the presence of apurinic/apyrimidinic (AP) sites were decreased by 30% and 35%, respectively, in Adv-Ogg1 transduced cells (P < 0.0001 and P < 0.005, respectively). In addition, the expression of base excision repair (BER) pathway members APE1 and DNA polymerase γ was upregulated by Adv-Ogg1 transduction. Cells overexpressing Ogg1 had increased membrane potential (P < 0.05) and decreased mitochondrial fragmentation (P < 0.005). The mtDNA content was found to be higher in cells with increased OGG1 (P < 0.005). The protein levels of fission and apoptotic factors such as DRP1, FIS1, cytoplasmic cytochrome c, activated caspase-3, and activated caspase-9 were lower in Adv-Ogg1 transduced cells. These observations suggest that Ogg1 overexpression may be an important mechanism to protect cardiac cells against oxidative stress damage.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Moises
authors.initials: M
authors.lastname: Torres-Gonzalez
authors.forename: Thomas
authors.initials: T
authors.lastname: Gawlowski
authors.forename: Heidi
authors.initials: H
authors.lastname: Kocalis
authors.forename: Brian T
authors.initials: BT
authors.lastname: Scott
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002316:Cardiotonic Agents / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000096:biosynthesis / Q000378:metabolism*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000096:biosynthesis; D034281:Dynamins / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D006333:Heart Failure / Q000201:enzymology; D051379:Mice; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress; D051381:Rats; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D004272:DNA, Mitochondrial; C503403:Fis1 protein, rat; D024101:Mitochondrial Proteins; D006147:Guanine; C078307:8-oxo-7,8-dihydrodeoxyguanine; D024483:Vitamin K 3; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045304:Cytochromes c; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; C519851:Dnm1l protein, rat; D034281:Dynamins; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: 8-oxoguanine glycosylase; apoptosis; mitochondrial DNA damage; mitochondrial function; oxidative stress