Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.
Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.
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DOI：
10.1042/bj20130029
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发表时间：
2013-10-15
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影响因子：
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通讯作者：
Ballinger SW
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文献类型：
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作者：
Fetterman JL;Zelickson BR;Johnson LW;Moellering DR;Westbrook DG;Pompilius M;Sammy MJ;Johnson M;Dunham-Snary KJ;Cao X;Bradley WE;Zhang J;Wei CC;Chacko B;Schurr TG;Kesterson RA;Dell'italia LJ;Darley-Usmar VM;Welch DR;Ballinger SW
功能失调的生物能量学已经成为许多慢性疾病如糖尿病和心血管疾病的关键特征。这导致了线粒体范例，其中已经提出线粒体DNA（mtDNA）序列变异有助于疾病易感性。在这项研究中，我们提出了一种新的动物模型的mtDNA多态性，线粒体核交换小鼠（MNX），其中来自C3 H/HeN小鼠的mtDNA已插入到C57/BL 6核背景，反之亦然，以测试这一概念。我们的数据显示C57/BL 6 mtDNA对心脏容量超负荷的病理应激的易感性的主要贡献，这与核背景无关。携带C57/BL 6 J mtDNA的线粒体相对于具有C3 H/HeN mtDNA的线粒体产生更多的活性氧（ROS）并且具有更高的线粒体膜电位，与核背景无关。我们认为这是与容量超负荷引起的生物能功能障碍增加相关的主要机制。总之，这些研究支持疾病易感性发展的“线粒体范例”，并表明mtDNA调节细胞生物能量学、线粒体活性氧产生和对心脏应激的易感性。
Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress.