Somatic alterations in mitochondrial DNA produce changes in cell growth and metabolism supporting a tumorigenic phenotype |
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Authors: | Jana JandovaMingjian Shi Kimberly G. NormanGeorge P. Stricklin James E. Sligh |
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Affiliation: | a Southern Arizona VA Healthcare System and Department of Medicine, Dermatology Division, Arizona Cancer Center, University of Arizona, Tucson, AZ, USAb VA Tennessee Valley Healthcare System, Dermatology Division of the Department of Medicine, and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA |
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Abstract: | There have been many reports of mitochondrial DNA (mtDNA) mutations associated with human malignancies. We have observed allelic instability in UV-induced cutaneous tumors at the mt-Tr locus encoding the mitochondrial tRNA for arginine. We examined the effects of somatic alterations at this locus by modeling the change in a uniform nuclear background by generating cybrids harboring allelic variation at mt-Tr. We utilized the naturally occurring mtDNA variation at mt-Tr within the BALB/cJ (BALB) and C57BL/6J (B6) strains of Mus musculus to transfer their mitochondria into a mouse ρ0 cell line that lacked its own mtDNA. The BALB haplotype containing the mt-Tr 9821insA allele produced significant changes in cellular respiration (resulting in lowered ATP production), but increased rates of cellular proliferation in cybrid cells. Furthermore, the mtDNA genotype associated with UV-induced tumors endowed the cybrid cells with a phenotype of resistance to UV-induced apoptosis and enhanced migration and invasion capabilities. These studies support a role for mtDNA changes in cancer. |
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Keywords: | mtDNA, mitochondrial DNA UV, Ultraviolet ROS, Reactive Oxidative Species DCFH2-DA, 2&prime , 7-dichlorodihydrofluorescein diacetate NAC, N-acetyl-L-cysteine Vit E, vitamin E Mito C, Mitomycin C ATP, Adenosine Triphosphate OXPHOS, oxidative phosphorylation SNP, single nucleotide polymorphism MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes DMDF, maternally inherited diabetes with or without deafness MM, mitochondrial myopathy DMEM, Dulbecco's Modified Eagle's Medium FBS, Fetal Bovine Serum BSA, bovine serum albumin DPBS, Dulbecco's Phosphate Buffered Saline HBSS, Hanks' Balanced Salt Solution 7-AAD, boldFont" >7-amino-actinomycin D |
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