Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background.
Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background.
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DOI：
10.1093/hmg/ddl457
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发表时间：
2007-02
影响因子：
3.5
通讯作者：
Yong-Gang Yao;Felicia M. Ellison;J. McCoy;Jichun Chen;N. Young
中科院分区：
文献类型：
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作者：
Yong-Gang Yao;Felicia M. Ellison;J. McCoy;Jichun Chen;N. Young
线粒体DNA（mtDNA）的改变和随之而来的线粒体功能丧失是线粒体衰老理论的基础。在这项研究中，我们系统地分析了2864个单个造血干细胞（HSC）和祖细胞的mtDNA控制区体细胞突变模式，这些造血干细胞和祖细胞是通过流式细胞术分选的Lin（-）Kit（+）CD 34（-）参数从年轻和老年C57 BL/6（B6）和BALB/cBy（BALB）小鼠中分离出来的，以验证HSC中累积的mtDNA突变与老化过程中HSC的功能性衰老有关的假设。与年轻B6小鼠相比，老年B6小鼠单个HSC中mtDNA突变水平增加（P=0.003）;而BALB小鼠中未观察到明显的年龄依赖性突变积累（老年vs年轻，P=0.202），年轻和老年BALB小鼠的突变水平与老年B6小鼠接近（P>0.280）。小鼠HSC中的细胞活性氧（ROS）与这些细胞中mtDNA突变的水平无关，尽管B6小鼠与BALB小鼠相比具有更高比例的ROS（-）细胞。单个造血干细胞的增殖实验表明，与BALB小鼠的细胞相比，B6细胞形成更大的集落，而与年龄和mtDNA突变负荷无关。我们推断，从我们的数据，年龄相关的线粒体DNA体细胞突变的积累在小鼠HSC的核遗传背景的影响，这些突变可能没有明显相关的细胞ROS含量或HSC衰老。
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.