Human Molecular Genetics Advance Access originally published online on December 21, 2006
Human Molecular Genetics 2007 16(3):286-294; 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
1 Hematology Branch and 2 Flow Cytometry Core Facility, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA
* To whom the correspondence should be addressed at: National Heart, Lung, and Blood Institute, NIH, Bldg 10 CRC, Rm 3E-5140, 10 Center Drive, Bethesda, MD 20892-1202, USA. Fax: +1 3014968396; Email: yaoy3{at}nhlbi.nih.gov/ ygyaozh{at}yahoo.com
Received October 8, 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 the 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 when compared with young B6 mice (P=0.003); 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 when 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 HSC senescence.
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