Mitochondrial gene expression changes in normal and mitochondrial mutant cells after exposure to ionizing radiation.
Mitochondrial DNA (mtDNA) contains 13 genes that encode proteins of the oxidative phosphorylation complex that are involved in ATP generation. Leber's optic atrophy and Leigh's syndrome are diseases that are caused by point mutations in the mitochondrial genome and that have phenotypes associated with energy deprivation. We hypothesized that energy deficiency from mitochondrial mutations in these cells leads to radiation hypersensitivity. Here we compared mitochondrial gene expression for the 13 mitochondrial protein-coding genes in two mitochondrial mutant cell lines, GM13740 (Leigh's syndrome) and GM10744 (Leber's optic atrophy) and a normal human lymphoblastoid cell line (GM15036) after X irradiation (0-4 Gy) 0 to 24 h postirradiation. Changes in gene expression were compared with cellular radiosensitivity. Statistically significant differences between Leigh's syndrome and normal cells were found in mitochondrial gene expression for all radiation doses and times that were commensurate with changes in radiation sensitivity. The data suggest that Leigh's syndrome cells have an impaired ability to repair radiation-induced DNA damage that results in radiation hypersensitivity. This may be attributable to mitochondrial dysfunction from reductions in mitochondrial gene expression and ATP generation, since Leigh's optic atrophy cells exhibit a mutation in the ATPase6 gene, which is an important component of Complex V of ATP synthase. In contrast, the mutation of the Leber's cells conferred radioresistance, which might be attributed to the mutation in the ND4 gene in the mitochondrial genome. The altered sensitivity of mitochondrial mutant cells to ionizing radiation can lead to decreased DNA repair, which may put individuals with mtDNA mutations at greater risk for cancer and other diseases.
Kulkarni
Rohan
R
Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202, USA.
Marples
Brian
B
Balasubramaniam
Mamtha
M
Thomas
Robert A
RA
Tucker
James D
JD
D000255:Adenosine Triphosphate / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000528:radiation effects*; D002455:Cell Division; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics*; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010085:Oxidative Phosphorylation; D016133:Polymerase Chain Reaction; D011839:Radiation, Ionizing
D004272:DNA, Mitochondrial; C468783:H2AX protein, human; D006657:Histones; D000255:Adenosine Triphosphate