Attenuation of UV-induced apoptosis by coenzyme Q10 in human cells harboring large-scale deletion of mitochondrial DNA.
Chronic progressive external ophthalmoplegia (CPEO) syndrome is one of the mitochondrial diseases caused by large-scale deletions in mitochondrial DNA (mtDNA) that impair the respiratory function of mitochondria and result in decreased production of ATP in affected tissues. In order to investigate whether CPEO-associated mtDNA mutations (i.e., 4,366-bp and 4,977-bp large-scale deletions) render human cells more vulnerable to apoptosis, we constructed cybrids carrying the deleted mtDNA. Assays for cell viability, DNA fragmentation, cytochrome c release, and caspase 3 activation revealed that UV irradiation at 20 J/m2 triggered apoptosis in all the cybrids. This treatment also produced elevated intracellular levels of reactive oxygen species (ROS). The rate of UV-induced cell death was more pronounced in the cybrids harboring mtDNA deletions than in the control cybrid with wild-type mtDNA. Subsequently, we evaluated the effect of coenzyme Q10 on the UV-triggered apoptosis. The results showed that after pretreatment of the cybrids with 100 microM coenzyme Q10 the UV-induced cell damage (i.e., ROS production and activation of caspase 3) was significantly reduced. Taken together, these findings suggest that large-scale deletions of mtDNA increased the susceptibility of human cells to the UV-triggered apoptosis and that coenzyme Q10 mitigated the damage; hence, it might potentially serve as a therapeutic agent to treat mitochondrial diseases resulting from mtDNA deletions.
Lee
Cheng-Feng
CF
Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
Liu
Chun-Yi
CY
Chen
Shu-Mei
SM
Sikorska
Marianna
M
Lin
Chen-Yu
CY
Chen
Tzu-Ling
TL
Wei
Yau-Huei
YH
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003067:Coenzymes; D045304:Cytochromes c / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004789:Enzyme Activation / Q000528:radiation effects; D017353:Gene Deletion; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014466:Ultraviolet Rays
D003067:Coenzymes; D004272:DNA, Mitochondrial; D014451:Ubiquinone; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C024989:coenzyme Q10