Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis

Department of Pharmacolgy, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
AJP Cell Physiology (Impact Factor: 3.78). 03/2008; 294(2):C413-22. DOI: 10.1152/ajpcell.00362.2007
Source: PubMed

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.

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    • "As mentioned, the mitochondria are the main source of ROS and thus also a vulnerable target to oxidative damage. Impairment of the mitochondrial membranes and proteins can generate even more ROS that could cause damage to the mitochondrial DNA and lead to cell death by apoptosis [23]. An important sensor for the initiation of apoptosis by oxidative stress is ASK-1. "
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    Oxidative Medicine and Cellular Longevity 01/2014; 2014(2):427318. DOI:10.1155/2014/427318 · 3.36 Impact Factor
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    • "This secondary production of ROS and lipid oxidation is most likely due to damage to the mitochondrial electron transport chain and/or the induction of NADPH oxidases. H2O2 has been shown to damage mitochondrial DNA and lipids as well as disrupt the electron transport chain, causing an increase in mitochondrial superoxide production [35], [36]. In addition, recent evidence has emerged implicating H2O2 as a signaling molecule capable of stimulating ROS production via NADPH oxidases [37], [38]. "
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    • "So, considering the critical role of oxidative stress in cardiac remodeling, we suggest that oxidative stress is associated with the cardiac dysfunction observed in our study. Oxidative stress has direct effects on cellular structure and function, and it can activate signaling molecules that are involved in cardiac remodeling, including apoptotic cascade [43], [44]. In previous studies, taurine has been shown to promote antioxidant activity, regulating the rate of ROS generation by the mitochondria [8]. "
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