Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis.
Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis.
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线粒体聚合酶缺陷的转基因小鼠模型表现出 IV 态呼吸减少和心脏纤维化增强。
DOI：
10.1038/labinvest.2012.146
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发表时间：
2013-02
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线粒体产生正常心脏收缩功能所需的能量，表现为线粒体电子传递减少的心肌细胞产生的能量减少，收缩能力降低。线粒体DNA(MtDNA)编码电子传递链(ETC)蛋白质复合体的核心亚基。线粒体DNA丰度降低与基因工程小鼠和人类疾病的ETC减少和心力衰竭的发展有关。针对艾滋病病毒/艾滋病的核苷逆转录酶抑制剂(NRTI)被用于抗逆转录病毒治疗，其通过抑制线粒体聚合酶(POLγ)而导致线粒体DNA丰度降低，作为一种限制性副作用。我们在一个已建立的转基因小鼠模型(TG)中探索了氮卓酮暴露对线粒体γ丰度的影响，在该模型中，心脏靶向突变形式的PolDNA表现为扩张型心肌病，左心室重量(LV)增加，左心室舒张末内径增加。TG和野生型小鼠每天服用0.22 mg AZT或赋形剂35天，随后分析生理、组织和分子变化。35天后，Y955C TGS出现不依赖AZT的心肌纤维化。在Y955C小鼠中观察到线粒体DNA丰度降低；AZT治疗对这种缺失没有影响，这表明Y955C足以最大限度地降低mtDNA丰度。经AZT处理的Y955C心脏分离的线粒体经血氧饱和度测量显示线粒体能量功能降低。AZT对Y955C突变的治疗进一步减少了基础线粒体呼吸和状态体外呼吸。综上所述，这些结果表明，POLγ功能缺陷会促进心肌病、心脏纤维化、线粒体DNA耗竭和线粒体能量产生减少。
Mitochondria produce the energy required for proper cardiac contractile function, and cardiomyocytes that exhibit reduced mitochondrial electron transport will have reduced energy production and decreased contractility. Mitochondrial DNA (mtDNA) encodes the core subunits for the protein complexes of the electron transport chain (ETC). Reduced mtDNA abundance has been linked to reduced ETC and the development of heart failure in genetically engineered mice and in human diseases. Nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS are used in antiretroviral regimens, which cause decreased mtDNA abundance by inhibiting the mitochondrial polymerase, pol γ as a limiting side effect. We explored consequences of AZT exposure on mtDNA abundance in an established transgenic mouse model (TG) in which a cardiac-targeted mutant form of pol γ displays a dilated cardiomyopathy (DCM) phenotype with increased left ventricle (LV) mass and increased LV end diastolic dimension. TG and wild-type littermate mice received 0.22mg/day AZT or vehicle for 35 days and subsequently analyzed for physiological, histological, and molecular changes. After 35 days, Y955C TGs exhibited cardiac fibrosis independent of AZT. Reduced mtDNA abundance was observed in the Y955C mouse; AZT treatment had no effect on that depletion suggesting that Y955C was sufficient to reduce mtDNA abundance maximally. Isolated mitochondria from AZT-treated Y955C hearts displayed reduced mitochondrial energetic function by oximetric measurement. AZT treatment of the Y955C mutation further reduced basal mitochondrial respiration and state IVo respiration. Together, these results demonstrate that defective pol γ function promotes cardiomyopathy, cardiac fibrosis, mtDNA depletion, and reduced mitochondrial energy production.
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影响因子：
20.1
作者：
Dai DF;Rabinovitch PS;Ungvari Z
通讯作者：
Ungvari Z
影响因子：
5
作者：
Kohler, James J.;Hosseini, Seyed H.;Lewis, William
通讯作者：
Lewis, William
影响因子：
2.9
作者：
Starcher, B
通讯作者：
Starcher, B
影响因子：
3.9
作者：
WOESSNER, JF
通讯作者：
WOESSNER, JF
影响因子：
5
作者：
Lewis, William;Day, Brian J.;Copeland, William C.
通讯作者：
Copeland, William C.