Enhanced oxidative damage in human cells harboring A3243G mutation of mitochondrial DNA: implication of oxidative stress in the pathogenesis of mitochondrial diabetes.
Mitochondrial oxidative phosphorylation and the ATP production in pancreatic beta cells play significant roles in insulin secretion in response to glucose and other nutrients. An A to G mutation in the tRNA(Leu(UUR)) gene at nucleotide position (np) 3243 of mitochondrial DNA (mtDNA) has been observed in patients with MELAS syndrome and mitochondrial diabetes. Recently, some patients with mitochondrial diabetes associated with the A3243G mtDNA mutation were found to respond to coenzyme Q10 therapy. Thus, we investigated oxidative stress and peroxidative damage in a series of cybrids carrying either the wild-type adenine or the mutant-type guanine at np 3243 but having otherwise identical mtDNA sequence. The cybrids harboring >90% of the A3243G mutant mtDNA were found to have significantly lower oxygen consumption rate and electron transfer activities, and thereby had lower ATP/ADP ratios and declined energy charge. Importantly, the defective respiratory function elicited by the A3243G mtDNA mutation caused an increased oxidative stress as indicated by the decreased GSH/GSSG ratio and enhanced oxidative damage to lipids. Moreover, the cybrids harboring high proportions of the A3243G mtDNA mutation were found to be much more vulnerable to an exogenous oxidant, tert-butylhydroperoxide. We thus suggest that enhanced oxidative damage and elevated oxidative stress contribute to the decline of mitochondrial function and may be involved in the initiation and progression of the MELAS syndrome and mitochondrial diabetes.
Pang
C Y
CY
Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, 112, Republic of China, Taipei, Taiwan.
Lee
H C
HC
Wei
Y H
YH
D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D003920:Diabetes Mellitus / Q000209:etiology* / Q000235:genetics; D004734:Energy Metabolism; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism; D017241:MELAS Syndrome / Q000235:genetics; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress; D010101:Oxygen Consumption; D012016:Reference Values; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D004272:DNA, Mitochondrial; D020122:tert-Butylhydroperoxide