title: Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis.
abstract: Recently, it has become apparent that mitochondrial DNA (mtDNA) damage can rapidly initiate apoptosis independent of mutations, although the mechanism involved remains unclear. To elucidate this mechanism, angiotensin II-mediated apoptosis was studied in cells that were transduced with a lentiviral vector to overexpress the DNA repair enzyme 8-oxoguanine glycosylase or were treated with inhibitors known to block angiotensin II-induced mtDNA damage. Cells exhibiting angiotensin II-induced mtDNA damage showed two phases of superoxide generation, the first derived from NAD(P)H oxidase and the second of mitochondrial origin, whereas cells prevented from experiencing mtDNA damage importantly exhibited only the first phase. Furthermore, cells with mtDNA damage demonstrated impairments in mitochondrial protein expression, cellular respiration, and complex 1 activity before the onset of the second phase of oxidation. After the second phase, the mitochondrial membrane potential collapsed, cytochrome c was released, and the cells underwent apoptosis, all of which were prevented by disrupting mtDNA damage. Collectively, these data reveal a novel mechanism of apoptosis that is initiated when mtDNA damage triggers mitochondrial superoxide generation and ultimately the activation of the mitochondrial permeability transition. This novel mechanism may play an important pathological role.
authors: Department of Pharmacolgy, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
authors: Craig
authors: C
authors: Ricci
authors: Viktor
authors: V
authors: Pastukh
authors: Josh
authors: J
authors: Leonard
authors: Julio
authors: J
authors: Turrens
authors: Glenn
authors: G
authors: Wilson
authors: David
authors: D
authors: Schaffer
authors: Stephen W
authors: SW
authors: Schaffer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D013481:Superoxides; D045304:Cytochromes c; D019255:NADPH Oxidases; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D010450:Endopeptidases; C047491:angiotensin-producing serum enzyme II