Identification of an mtDNA mutation hot spot in UV-induced mouse skin tumors producing altered cellular biochemistry.
There is increasing awareness of the role of mtDNA alterations in the development of cancer, as mtDNA point mutations are found at high frequency in a variety of human tumors. To determine the biological effects of mtDNA mutations in UV-induced skin tumors, hairless mice were irradiated to produce tumors, and the tumor mtDNAs were screened for single-nucleotide changes using temperature gradient capillary electrophoresis (TGCE), followed by direct sequencing. A mutation hot spot (9821insA) in the mitochondrially encoded tRNA arginine (mt-Tr) locus (tRNA(Arg)) was discovered in approximately one-third of premalignant and malignant skin tumors. To determine the functional relevance of this particular mutation in vitro, cybrid cell lines containing different mt-Tr (tRNA(Arg)) alleles were generated. The resulting cybrid cell lines contained the same nuclear genotype and differed only in their mtDNAs. The biochemical analysis of the cybrids revealed that the mutant haplotype is associated with diminished levels of complex I protein (CI), resulting in lower levels of baseline oxygen consumption and lower cellular adenosine triphosphate (ATP) production. We hypothesize that this specific mtDNA mutation alters cellular biochemistry, supporting the development of keratinocyte neoplasia.
Department of Medicine, Dermatology Division, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
Jana
J
Jandova
Alex
A
Eshaghian
Mingjian
M
Shi
Meiling
M
Li
Lloyd E
LE
King
Jaroslav
J
Janda
James E
JE
Sligh
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism; D010101:Oxygen Consumption; D012347:RNA, Transfer, Arg / Q000737:chemistry / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
D004272:DNA, Mitochondrial; D012347:RNA, Transfer, Arg; D000255:Adenosine Triphosphate