Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species
Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species
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DOI：
10.1073/pnas.1303046110
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发表时间：
2013-11-26
影响因子：
11.1
通讯作者：
Braun, Thomas
中科院分区：
文献类型：
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作者：
Pohjoismaeki, Jaakko L. O.;Williams, Sion L.;Braun, Thomas
成年人心脏线粒体DNA（mtDNA）的特征是由未知生物学意义的连接分子连接在一起的复杂分子形式。这些连接不存在于小鼠心脏中，并在人类出生后发育过程中出现，伴随着对氧化代谢的需求增加。为了分析心肌细胞中线粒体DNA组织在氧化应激过程中的作用，我们使用了小鼠模型，该模型通过线粒体解旋酶TWINKLE的过表达来重现人类心脏的复杂线粒体DNA组织。TWINKLE的过表达挽救了氧化损伤诱导的mtDNA复制停滞，减少了mtDNA点突变负荷，并在杂合子线粒体超氧化物歧化酶敲除心脏中修饰了mtDNA重排，以及以p21依赖的方式改善了超氧化物歧化酶敲除小鼠的心肌病。我们的结论是，线粒体DNA的完整性影响细胞的生存和原因，组织特异性模式的线粒体DNA的维护代表了适应氧化应激。
Mitochondrial DNA (mtDNA) in adult human heart is characterized by complex molecular forms held together by junctional molecules of unknown biological significance. These junctions are not present in mouse hearts and emerge in humans during postnatal development, concomitant with increased demand for oxidative metabolism. To analyze the role of mtDNA organization during oxidative stress in cardiomyocytes, we used a mouse model, which recapitulates the complex mtDNA organization of human hearts by overexpression of the mitochondrial helicase, TWINKLE. Overexpression of TWINKLE rescued the oxidative damage induced replication stalling of mtDNA, reduced mtDNA point mutation load, and modified mtDNA rearrangements in heterozygous mitochondrial superoxide dismutase knockout hearts, as well as ameliorated cardiomyopathy in mice superoxide dismutase knockout in a p21-dependent manner. We conclude that mtDNA integrity influences cell survival and reason that tissue specific modes of mtDNA maintenance represent an adaptation to oxidative stress.