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

Jason F. Harrison; Scott B. Hollensworth; Douglas R. Spitz; William C. Copeland; Glenn L. Wilson; Susan P. LeDoux

doi:10.1093/nar/gki759

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

Journal article

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

Jason F. Harrison, Scott B. Hollensworth, Douglas R. Spitz, William C. Copeland, Glenn L. Wilson and Susan P. LeDoux

Nucleic acids research, Vol.33(14), pp.4660-4671

01/01/2005

DOI: 10.1093/nar/gki759

PMCID: PMC1187820

PMID: 16107556

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Abstract

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 γ 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.

Details

Title: Subtitle: Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance
Creators: Jason F. Harrison - University of South Alabama
Scott B. Hollensworth
Douglas R. Spitz - University of Iowa
William C. Copeland - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences
Glenn L. Wilson
Susan P. LeDoux
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.33(14), pp.4660-4671
DOI: 10.1093/nar/gki759
PMID: 16107556
PMCID: PMC1187820
NLM abbreviation: Nucleic Acids Res
ISSN: 0305-1048
eISSN: 1362-4962
Publisher: Oxford University Press
Language: English
Date published: 01/01/2005
Academic Unit: Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984312980002771

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