The DNA glycosylase Ogg1 defends against oxidant-induced mtDNA damage and apoptosis in pulmonary artery endothelial cells.
Emerging evidence suggests that mitochondrial (mt) DNA damage may be a trigger for apoptosis in oxidant-challenged pulmonary artery endothelial cells (PAECs). Understanding the rate-limiting determinants of mtDNA repair may point to new targets for intervention in acute lung injury. The base excision repair (BER) pathway is the only pathway for oxidative damage repair in mtDNA. One of the key BER enzymes is Ogg1, which excises the base oxidation product 8-oxoguanine. Previously we demonstrated that overexpression of mitochondrially targeted Ogg1 in PAECs attenuated apoptosis induced by xanthine oxidase (XO) treatment. To test the idea that Ogg1 is a potentially rate-limiting BER determinant protecting cells from oxidant-mediated death, PAECs transfected with siRNA to Ogg1 were challenged with XO and the extent of mitochondrial and nuclear DNA damage was determined along with indices of apoptosis. Transfected cells demonstrated significantly reduced Ogg1 activity, which was accompanied by delayed repair of XO-induced mtDNA damage and linked to increased XO-mediated apoptosis. The nuclear genome was undamaged by XO in either control PAECs or cells depleted of Ogg1. These observations suggest that Ogg1 plays a critical and possibly rate-limiting role in defending PAECs from oxidant-induced apoptosis by limiting the persistence of oxidative damage in the mitochondrial genome.
Department of Pharmacology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Mykhaylo V
MV
Ruchko
Olena M
OM
Gorodnya
Andres
A
Zuleta
Viktor M
VM
Pastukh
Mark N
MN
Gillespie
D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D019610:Cytoprotection / Q000235:genetics; D004249:DNA Damage; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D015870:Gene Expression; D020868:Gene Silencing; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D019271:Hypoxanthine / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000009:adverse effects* / Q000378:metabolism; D018384:Oxidative Stress; D011651:Pulmonary Artery / Q000166:cytology / Q000201:enzymology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014969:Xanthine Oxidase / Q000009:adverse effects / Q000378:metabolism
D004272:DNA, Mitochondrial; D016877:Oxidants; D034741:RNA, Small Interfering; D019271:Hypoxanthine; C024829:8-hydroxyguanine; D006147:Guanine; D014969:Xanthine Oxidase; D045647:DNA Glycosylases; C483741:OGG1 protein, rat