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Nucleic Acids Research 2005 33(14):4660-4671; doi:10.1093/nar/gki759
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Published online 17 August 2005

©The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance

Jason F. Harrison, Scott B. Hollensworth, Douglas R. Spitz1, William C. Copeland2, Glenn L. Wilson and Susan P. LeDoux*

Department of Cell Biology and Neuroscience, University of South Alabama Mobile, AL 36688, USA 1Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, The University of Iowa IA City, IA 52242, USA 2Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences Research Triangle Park, NC 27709, USA

*To whom correspondence should be addressed. Tel: +1 251 460 6762; Fax: +1 251 414 8241; Email: sledoux{at}usouthal.edu

Received May 26, 2005. Revised July 21, 2005. Accepted July 21, 2005.

Neurodegeneration can occur as a result of endogenous oxidative stress. Primary cerebellar granule cells were used in this study to determine if mitochondrial DNA (mtDNA) repair deficiencies correlate with oxidative stress-induced apoptosis in neuronal cells. Granule cells exhibited a significantly higher intracellular oxidative state compared with primary astrocytes as well as increases in reductants, such as glutathione, and redox sensitive signaling molecules, such as AP endonuclease/redox effector factor-1. Cerebellar granule cultures also exhibited an increased susceptibility to exogenous oxidative stress. Menadione (50 µM) produced twice as many lesions in granule cell mtDNA compared with astrocytes, and granule cell mtDNA repair was significantly less efficient. A decreased capacity to repair oxidative mtDNA damage correlates strongly with mitochondrial initiated apoptosis in these neuronal cultures. Interestingly, the mitochondrial activities of initiators for base excision repair (BER), the bifunctional glycosylase/AP lyases as well as AP endonuclease, were significantly higher in cerebellar granule cells compared with astrocytes. The increased mitochondrial AP endonuclease activity in combination with decreased polymerase {gamma} activity may cause an imbalance in oxidative BER leading to an increased production and persistence of mtDNA damage in neurons when treated with menadione. This study provides evidence linking neuronal mtDNA repair capacity with oxidative stress-related neurodegeneration.


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