Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics.
Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics.
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线粒体DNA多态性的鉴定会改变线粒体基质pH和细胞内钙动力学。
DOI：
10.1371/journal.pgen.0020128
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发表时间：
2006-08
期刊：
影响因子：
4.5
通讯作者：
Kato, Tadafumi
中科院分区：
文献类型：
--
作者：
Kazuno, An-a;Munakata, Kae;Nagai, Takeharu;Shimozono, Satoshi;Tanaka, Masashi;Yoneda, Makoto;Kato, Nobumasa;Miyawaki, Atsushi;Kato, Tadafumi
线粒体DNA(MtDNA)是高度多态的，它在人类中的变异可能导致功能的个体差异以及对各种疾病的易感性，如帕金森病、阿尔茨海默病、双相情感障碍和癌症。然而，线粒体DNA多态是否以及如何影响细胞内的功能，如钙信号或pH调节，目前尚不清楚。在这里，我们使用携带比率计量型Pericam(RP)的传递线粒体杂交细胞(Cybrids)来寻找具有细胞内功能意义的mtDNA多态性。通过对35个杂交种mtDNA全序列的分析，我们发现两个紧密连锁的非同义多态8701A和10398A增加了线粒体靶向RP的基础荧光比率。8701A/10398A的线粒体基质pH低于8701G/10398G的线粒体基质pH，提示线粒体钙离子水平的改变是造成这种差异的主要原因。8701A/10398A的胞内钙离子对组胺的反应性也较高。此前有报道称，10398A与患帕金森病、阿尔茨海默病、躁郁症和癌症的风险增加有关，而10398G与长寿有关。我们的发现提示这些mtDNA多态可能通过影响线粒体基质pH和细胞内钙动力学而在这些复杂疾病的病理生理学中发挥作用。线粒体在能量生产和细胞内钙水平的调节中起着重要作用。线粒体有自己的遗传物质，线粒体DNA(MtDNA)。尽管线粒体DNA的长度很短(16kbp)，但它在不同个体之间存在很大的差异，被认为是智力和运动表现等需要能量的活动中个体间功能差异的原因。然而，线粒体DNA的多态是否会影响细胞内的功能和状态尚不清楚。利用传递线粒体杂交细胞，作者发现了两个紧密连锁的mtDNA多态，10398A/G和8701A/G，导致线粒体pH和钙浓度的变化。携带这两种mtDNA多态的传递线粒体杂交细胞对组胺的胞浆钙反应趋于不同。据报道，10398A基因多态是帕金森病、阿尔茨海默病、癌症和双相情感障碍的危险因素，而10398G与长寿有关。提示线粒体DNA多态可能通过影响线粒体基质pH和细胞内钙动力学而在这些复杂疾病的病理生理过程中发挥作用。
Mitochondrial DNA (mtDNA) is highly polymorphic, and its variations in humans may contribute to individual differences in function as well as susceptibility to various diseases such as Parkinson disease, Alzheimer disease, bipolar disorder, and cancer. However, it is unclear whether and how mtDNA polymorphisms affect intracellular function, such as calcium signaling or pH regulation. Here we searched for mtDNA polymorphisms that have intracellular functional significance using transmitochondrial hybrid cells (cybrids) carrying ratiometric Pericam (RP), a fluorescent calcium indicator, targeted to the mitochondria and nucleus. By analyzing the entire mtDNA sequence in 35 cybrid lines, we found that two closely linked nonsynonymous polymorphisms, 8701A and 10398A, increased the basal fluorescence ratio of mitochondria-targeted RP. Mitochondrial matrix pH was lower in the cybrids with 8701A/10398A than it was in those with 8701G/10398G, suggesting that the difference observed by RP was mainly caused by alterations in mitochondrial calcium levels. Cytosolic calcium response to histamine also tended to be higher in the cybrids with 8701A/10398A. It has previously been reported that 10398A is associated with an increased risk of Parkinson disease, Alzheimer disease, bipolar disorder, and cancer, whereas 10398G associates with longevity. Our findings suggest that these mtDNA polymorphisms may play a role in the pathophysiology of these complex diseases by affecting mitochondrial matrix pH and intracellular calcium dynamics. Mitochondria play important roles in energy production and regulation of intracellular calcium levels. Mitochondria have their own genetic material, mitochondrial DNA (mtDNA). In spite of its short length (16 kbp), mtDNA is highly variable among individuals and is thought to contribute to interindividual functional variability in energy-requiring activities such as intelligence and athletic performance. However, it is unclear whether mtDNA polymorphisms affect intracellular function and condition. Using transmitochondrial hybrid cells, the authors found two closely linked mtDNA polymorphisms, 10398A/G and 8701A/G, which cause alterations in mitochondrial pH and calcium concentration. Cytosolic calcium response to histamine tended to be different between transmitochondrial hybrid cells carrying these two mtDNA polymorphisms. It has been reported that the 10398A mtDNA polymorphism is a risk factor for Parkinson disease, Alzheimer disease, cancer, and bipolar disorder, whereas 10398G is associated with longevity. The present findings suggest that these mtDNA polymorphisms may play a role in the pathophysiology of these complex diseases by affecting mitochondrial matrix pH and intracellular calcium dynamics.
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通讯作者：
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