Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ
Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ
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DOI：
10.1038/labinvest.3700523
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发表时间：
2007-04-01
影响因子：
5
通讯作者：
Copeland, William C.
中科院分区：
文献类型：
--
作者：
Lewis, William;Day, Brian J.;Copeland, William C.
Polg是一种人类基因，编码人类线粒体DNA(MtDNA)的复制酶DNA聚合酶伽马催化亚单位(POL伽马)。Polg Y955C点突变导致人类慢性进行性眼外肌麻痹(CPEO)，这是一种伴有眼肌无力和mtDNA缺陷的线粒体疾病。Y955C Polg转基因靶向(Tg)小鼠心脏。确定了4个TG(+/-)品系和野生型(WT)窝产仔(-/-)的存活率。左心室功能(超声心动图和核磁共振)、心率(心电图学)、线粒体DNA丰度(实时定量聚合酶链式反应)、线粒体DNA氧化(8-OHdG)、组织病理学和电子显微镜确定了表型。心脏靶向Y955C Polg在患有心肌病(CM)、线粒体氧化应激和过早死亡的心脏中产生CPEO的分子特征。LV腔大小和LV质量增加，心动过缓，mtDNA减少，8-OHdG增加，心脏组织病理学和线粒体EM缺陷支持和定义表型。这项研究强调了人类突变Polg及其基因产物在线粒体DNA耗竭、线粒体氧化应激和CM中的致病作用，因为它与CPEO的遗传缺陷有关。转基因模型在病理生理学上将人类突变体Pol-Gamma、线粒体DNA耗竭和线粒体氧化应激与线粒体DNA复制装置和CM联系起来。
POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild- type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance ( real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8- OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.