Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance.
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 muM) 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.
Harrison
Jason F
JF
Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, AL 36688, USA.
Hollensworth
Scott B
SB
Spitz
Douglas R
DR
Copeland
William C
WC
Wilson
Glenn L
GL
LeDoux
Susan P
SP
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D004272:DNA, Mitochondrial; D045643:DNA Repair Enzymes