TY - JOUR
T1 - The relationship between the aging- and photo-dependent T414G mitochondrial DNA mutation with cellular senescence and reactive oxygen species production in cultured skin fibroblasts
AU - Birket, Matthew J.
AU - Passos, Joo F.
AU - Von Zglinicki, Thomas
AU - Birch-Machin, Mark A.
N1 - Funding Information:
This work was made possible by the generous support of the Biotechnology and Biological Sciences Research Council (BBSRC) (BBSRC CASE award with Unilever). We are grateful to Dr C. Lawrence, Dr J. Langtree, and the patients of the Royal Victoria Infirmary Dermatology Out-Patients Clinic for their help in this study.
PY - 2009/6
Y1 - 2009/6
N2 - Mutations in the mitochondrial genome (mtDNA) are thought to be one of the causes of age-dependent cellular decline through their detrimental effects on respiration or reactive oxygen species (ROS) production. However, for many mutations, this link has not been clearly established. This study aimed to further investigate the phenotypic importance of a T414G mutation within the control region of mtDNA, previously shown to accumulate in both chronologically and photoaged human skin. We demonstrate that during dermal skin fibroblast replication in vitro in five separate cultures obtained from elderly individuals, the T414G mutant load can either increase or decrease during progressive cell division, implying the absence of consistent selection against the mutation in this context. In support of this, by utilizing a cell-sorting approach, we demonstrate that the level of the T414G mutation does not directly correlate with increased or decreased mtDNA copy number, or markers of cellular ageing including lipofuscin accumulation or ROS production. By consequence, the mutation can be distributed with a bias towards either the proliferating or senescent cell populations depending on the cell line. In conclusion, we propose that this particular mutation may have little effect on ROS production and the onset of cellular senescence in cultured fibroblasts.
AB - Mutations in the mitochondrial genome (mtDNA) are thought to be one of the causes of age-dependent cellular decline through their detrimental effects on respiration or reactive oxygen species (ROS) production. However, for many mutations, this link has not been clearly established. This study aimed to further investigate the phenotypic importance of a T414G mutation within the control region of mtDNA, previously shown to accumulate in both chronologically and photoaged human skin. We demonstrate that during dermal skin fibroblast replication in vitro in five separate cultures obtained from elderly individuals, the T414G mutant load can either increase or decrease during progressive cell division, implying the absence of consistent selection against the mutation in this context. In support of this, by utilizing a cell-sorting approach, we demonstrate that the level of the T414G mutation does not directly correlate with increased or decreased mtDNA copy number, or markers of cellular ageing including lipofuscin accumulation or ROS production. By consequence, the mutation can be distributed with a bias towards either the proliferating or senescent cell populations depending on the cell line. In conclusion, we propose that this particular mutation may have little effect on ROS production and the onset of cellular senescence in cultured fibroblasts.
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U2 - 10.1038/jid.2008.373
DO - 10.1038/jid.2008.373
M3 - Article
C2 - 19052564
AN - SCOPUS:67349231565
SN - 0022-202X
VL - 129
SP - 1361
EP - 1366
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 6
ER -