Mitochondrial mutant cells are hypersensitive to ionizing radiation, phleomycin and mitomycin C.
Mitochondrial DNA (mtDNA) is an important contributor to the ATP-generating oxidative phosphorylation complex. Single nucleotide mutations in mitochondrial genes involved in ATP synthesis result in a broad range of diseases. Leber optic atrophy and Leigh's syndrome are two such diseases arising from point mutations in the mitochondrial genome. Here, ionizing radiation, phleomycin and mitomycin C (MMC) were used to induce structural chromosomal aberrations in Leber's and Leigh's cells to investigate how these mitochondrial mutations affect the cell's DNA repair processes. Because of the energy deprivation that results from mitochondrial mutations, we hypothesized that these mutant cells would demonstrate hypersensitivity when exposed to oxidative and genotoxic stress and we also expected that these cells would not be able to repair nuclear DNA damage as efficiently as normal cells. As a consequence, these mutant cells are expected to show increased levels of DNA damage, longer cell cycle delays and increased levels of cell death. Following acute radiation exposure these mutant cells showed an increase in the number of chromosomal aberrations and decreased mitotic indices when compared with normal human lymphoblastoid cells with wild-type mtDNA. When exposed to phleomycin or MMC, the mitochondrial mutant cells again showed hypersensitivity and decreased mitotic indices compared to normal cells. These results suggest that Leber's and Leigh's cells have an impaired ability to cope with oxidative and genotoxic stress. These observations may help explain the role of ATP generation in understanding the enhanced sensitivity of mitochondrial mutant cells to cancer therapeutic agents and to adverse environmental exposure, suggesting that individuals with mtDNA mutations may be at a greater risk for cancer and other diseases that result from an accumulation of nuclear DNA damage.
Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.
Rohan
R
Kulkarni
Adrian
A
Reither
Robert A
RA
Thomas
James D
JD
Tucker
D002460:Cell Line; D002869:Chromosome Aberrations / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D016685:Mitomycin / Q000494:pharmacology*; D008940:Mitotic Index; D009154:Mutation / Q000235:genetics*; D010692:Phleomycins / Q000494:pharmacology*; D011839:Radiation, Ionizing
D010692:Phleomycins; D016685:Mitomycin