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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/C413    most recent 00362.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ricci, C. Articles by Schaffer, S. W. PubMed PubMed Citation Articles by Ricci, C. Articles by Schaffer, S. W.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis

¹Departments of Pharmacology, ²Biomedical Sciences, and ³Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama; and ⁴Department of Chemical Engineering, University of California at Berkeley, Berkeley, California

Submitted 13 August 2007 ; accepted in final form 10 December 2007

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.

angiotensin II; mitochondrial permeability transition pore; NADPH oxidase