Mutagenesis vol. 18 no. 6 pp. 497-503,
November 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus
1Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 212312, USA, 2Department of Life Sciences and Chemistry, Roskilde University, 4000 Roskilde, Denmark, 3Free Radical and Radiation Biology Graduate Program, B180 Medical Laboratories, The University of Iowa, Iowa City, IA 52242, USA and 4Department of Cancer Genetics, Roswell Park Cancer Institute, Cell and Virus Building, Room 247, Elm and Carlton Streets, Buffalo, NY 14263, USA
5Present address: Department of Radiation Oncology, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA
Depletion of the mitochondrial genome is involved in several human diseases, as well as in mitochondrial diseases induced by drug therapies used in the treatment of cancer and human immunodeficiency virus. In order to identify the molecular changes underlying the pathogenesis of mitochondrial diseases, we determined the oxidative status of a human cell line following depletion of the mitochondrial genome (denoted 
0 cells). Our analysis revealed that 0 cells contained 
10-fold lower levels of superoxide than parental cells (+), as detected by oxidation of dihydroethidium. No concurrent decrease in oxidation of hydrogen peroxide, detected using the dye dichloroflorescein diacetate, was observed in 0 cells. Depletion of the mitochondrial genome did not affect either the expression of superoxide dismutase or its activity. However, catalase expression and its activity decreased in 0 cells. In addition, glutathione peroxidase activity was higher in 0 cells compared with +. 0 cells showed increased lipid peroxidation, increased oxidative damage to the nuclear genome and impaired DNA repair. Our data illustrate the importance of the mitochondrial genome and its function to the cellular oxidative environment and nuclear genome instability. It also provides insights into the development of mitochondrial disease as a consequence of cancer therapy.
6To whom correspondence should be addressed. Tel: +1 716 845 8017; Fax: +1 716 845 1047; Email: keshav.singh{at}roswellpark.org
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