Lactic acidemia in the pathogenesis of mice carrying mitochondrial DNA with a deletion
Lactic acidemia in the pathogenesis of mice carrying mitochondrial DNA with a deletion
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DOI：
10.1093/hmg/ddq228
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发表时间：
2010-08-15
影响因子：
3.5
通讯作者：
Hayashi, Jun-Ichi
中科院分区：
文献类型：
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作者：
Ogasawara, Emi;Nakada, Kazuto;Hayashi, Jun-Ichi
乳酸血症是由线粒体DNA突变引起的线粒体疾病的表现之一。然而，关于其在线粒体疾病表型进展中的慢性作用知之甚少。为了获得关于这一点的实验证据，我们使用了野生型和缺失型mtDNA（delta mtDNA）的跨线粒体模型小鼠（mito-mice）异质性。主要携带delta线粒体DNA的线粒体小鼠表现出线粒体呼吸缺陷和由此产生的疾病表型，包括乳酸血症;它们还表现出由过氧化物酶体增殖激活受体γ、辅激活因子1 α（PGC 1 alpha）介导的途径调节的线粒体生物合成减少，例如线粒体转录因子A和线粒体DNA编码的基因产物的表达以及线粒体DNA含量的控制。二氯乙酸钠（DCA）可抑制线粒体乳酸的加速生成，从而改善线粒体生物合成的下降，缓解线粒体呼吸缺陷，延长寿命。这些结果表明，在线粒体疾病中由代谢适应引起的乳酸的慢性过量产生进一步使线粒体功能失调。因此，线粒体疾病中的线粒体呼吸缺陷不仅直接由突变mtDNA的存在引起，而且还由慢性乳酸血症引起。我们的体内研究还表明，抑制慢性乳酸血症是治疗某些线粒体疾病的潜在策略。
Lactic acidemia is one manifestation of the mitochondrial diseases caused by pathogenic mutant mitochondrial DNA (mtDNA). However, little is known about its chronic effects in the progression of mitochondrial disease phenotypes. To obtain experimental evidence on this point, we used trans-mitochondrial model mice (mito-mice) heteroplasmic for wild-type and deleted mtDNA (delta mtDNA). Mito-mice carrying predominantly delta mtDNA showed mitochondrial respiration defects and the resultant disease phenotypes, including lactic acidemia; they also showed a decrease in mitochondrial biogenesis regulated by the peroxisome proliferative activated receptor gamma, coactivator 1 alpha (PGC1 alpha)-mediated pathway, such as the expression of mitochondrial transcription factor A and mtDNA-encoded gene products and the control of mtDNA content. When the accelerated lactate production of these mito-mice was pharmacologically inhibited by sodium dichloroacetate (DCA), the decrease in mitochondrial biogenesis improved, thus leading to the relaxation of mitochondrial respiration defects and extension of life span. These results showed that chronic overproduction of lactate caused by metabolic adaptation in mitochondrial diseases further deconditioned mitochondrial function. Mitochondrial respiration defects in mitochondrial diseases are therefore induced not only directly by the presence of mutant mtDNA, but also by the chronic lactic acidemia. Our in vivo study also suggested that inhibition of chronic lactic acidemia is a potential strategy for treating some mitochondrial diseases.