Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19408-13. doi: 10.1073/pnas.1303046110. Epub 2013 Nov 11.
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.
成人心脏中的线粒体 DNA（mtDNA）的特征是具有复杂的分子形式，这些分子形式由连接分子连接在一起，而这些连接分子的生物学意义尚不清楚。这些连接分子不存在于小鼠心脏中，而是在人类出生后发育过程中出现，与氧化代谢需求增加同时出现。为了分析 mtDNA 组织在心肌细胞氧化应激中的作用，我们使用了一种小鼠模型，该模型通过过度表达线粒体解旋酶 TWINKLE 来重现人类心脏中复杂的 mtDNA 组织。TWINKLE 的过表达挽救了 mtDNA 复制停滞引起的氧化损伤，降低了 mtDNA 点突变负荷，并改变了杂合子线粒体超氧化物歧化酶敲除心脏中的 mtDNA 重排，以及以 p21 依赖性方式改善了超氧化物歧化酶敲除小鼠的心肌病。我们得出结论，mtDNA 的完整性会影响细胞的存活，因此组织特异性的 mtDNA 维持模式代表了对氧化应激的适应。
