Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.
Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.
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DOI：
10.1534/g3.113.007245
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发表时间：
2013-09-04
期刊：
影响因子：
--
通讯作者：
Nakada K
中科院分区：
文献类型：
--
作者：
Katada S;Mito T;Ogasawara E;Hayashi J;Nakada K
对患者的研究表明，一些线粒体疾病的临床表型可能从一种疾病转变为另一种疾病（例如，皮尔森综合征[PS]到Kearns-Sayre综合征），但没有直接的实验证据。为了确定线粒体DNA是否具有诱导多种线粒体疾病表型的病理潜力，我们使用了具有野生型mtDNA和线粒体DNA异质状态的trans-mitochondrial小鼠（mito-mice cytoplasmic）。携带≥50%线粒体DNA的晚期胚胎表现出部分类似于PS（PS样表型）的肝脏造血和铁代谢异常，尽管它们不表达PS的典型症状铁粒幼细胞性贫血。超过一半的新生儿与PS样表型出生后1个月死亡，而其余的表现出的受影响的组织，外周血和肝脏中的线粒体DNA载量减少，他们从PS样表型恢复。存活的线粒体小鼠不同组织中线粒体DNA的比例随着时间的推移而增加，当线粒体DNA在不同组织中的比例达到>70- 80%时，就会出现Kearns-Sayre综合征样表型。我们的模型小鼠研究清楚地表明，一个单一的线粒体DNA是负责至少两个不同的疾病表型在不同的年龄，并建议，在受影响的组织中的线粒体mtDNA负载的水平和动态将是重要的线粒体疾病表型的发病和转变在小鼠。
Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.
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影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
影响因子：
3.5
作者：
Ogasawara, Emi;Nakada, Kazuto;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
64.8
作者：
HOLT, IJ;HARDING, AE;MORGANHUGHES, JA
通讯作者：
MORGANHUGHES, JA
影响因子：
30.8
作者：
Inoue, K;Nakada, K;Hayashi, JI
通讯作者：
Hayashi, JI
影响因子：
3
作者：
DiMauro, S.;Garone, C.
通讯作者：
Garone, C.