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Human Molecular Genetics Advance Access published online on December 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl457
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Published by Oxford University Press 2006

Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background

Yong-Gang Yao1,*, Felicia M. Ellison1, J. Philip McCoy, Jr.2, Jichun Chen1 and Neal S. Young1

1 Hematology Branch 2 Flow Cytometry Core Facility, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892

* Corresponding author: Dr. Yong-Gang Yao National Heart, Lung, and Blood Institute, NIH Bldg 10 CRC, Rm 3E-5140, 10 Center Drive, Bethesda, MD, 20892-1202 Fax: +1 301 496 8396 E-mail: yaoy3{at}nhlbi.nih.gov or ygyaozh{at}yahoo.com

Received October 8, 2006; Revised November 28, 2006; Accepted December 4, 2006

Alterations in mitochondrial DNA (mtDNA) and consequent loss of mitochondrial function underlie the mitochondrial theory of aging. In this study, we systematically analyzed mtDNA control region somatic mutation pattern in 2864 single hematopoietic stem cells (HSCs) and progenitors, isolated by flow cytometry sorting on Lin–Kit+CD34– parameters from young and old C57BL/6 (B6) and BALB/cBy (BALB) mice, to test the hypothesis that the accumulated mtDNA mutations in HSCs were strain-correlated and associated with HSC functional senescence during aging. An increased level of mtDNA mutations in single HSCs was observed in old B6 as compared with young B6 mice (P =0.003 < 0.05); in contrast, no significant age-dependent accumulation of mutations was observed in BALB mice (old versus young, P = 0.202) and the level of mutations in both young and old BALB mice was close to that of old B6 mice (P > 0.280). Cellular reactive oxygen species (ROS) in mouse HSCs could not be correlated with the level of mtDNA mutations in these cells, although B6 mice had a higher proportion of ROS– cells compared with the BALB mice. Propagation assays of single HSCs showed B6 cells form larger colonies compared with cells from BALB mice, irrespective of age and mtDNA mutation load. We infer from our data that age-related mtDNA somatic mutation accumulation in mouse HSCs is influenced by the nuclear genetic background, and that these mutations may not obviously correlate to either cellular ROS content or senescence of HSCs.


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