Role of nitric oxide-induced mtDNA damage in mitochondrial dysfunction and apoptosis.
An increasing body of evidence suggests that nitric oxide (NO) can be cytotoxic and induce apoptosis. NO can also be genotoxic and cause DNA damage and mutations. It has been shown that NO damages mitochondrial DNA (mtDNA) to a greater extent than nuclear DNA. Previously, we reported that conditional targeting of the DNA repair protein hOGG1 into mitochondria using a mitochondria targeting sequence (MTS) augmented mtDNA repair of oxidative damage and enhanced cellular survival. To determine whether enhanced repair resulting from augmented expression of hOGG1 could also protect against the deleterious effects of NO, we used HeLa TetOff/MTS-OGG1-transfected cells to conditionally express hOGG1 in mitochondria. The effects of additional hOGG1 expression on repair of NO-induced mtDNA damage and cell survival were evaluated. These cells, along with vector transfectants, in either the presence or absence of doxycycline (Dox), were exposed to NO produced by the rapid decomposition of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (PAPA NONOate). Functional studies revealed that cells expressing recombinant hOGG1 were more proficient at repairing NO-induced mtDNA damage, which led to increased cellular survival following NO exposure. Moreover, the results described here show that conditional expression of hOGG1 in mitochondria decreases NO-induced inhibition of ATP production and protects cells from NO-induced apoptosis.
Rachek
Lyudmila I
LI
Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, 36688, USA.
Grishko
Valentina I
VI
Ledoux
Susan P
SP
Wilson
Glenn L
GL
D017209:Apoptosis / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000187:drug effects*; D004318:Doxycycline / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D009569:Nitric Oxide / Q000494:pharmacology / Q000633:toxicity*
D004272:DNA, Mitochondrial; D006834:Hydrazines; C112653:PAPA NONOate; D009569:Nitric Oxide; D045304:Cytochromes c; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D004318:Doxycycline