Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels.
Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels.
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DOI：
10.1016/j.fob.2015.03.008
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发表时间：
2015
期刊：
影响因子：
2.6
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Kodaira, Masaki;Hatakeyama, Hideyuki;Yuasa, Shinsuke;Seki, Tomohisa;Egashira, Toru;Tohyama, Shugo;Kuroda, Yusuke;Tanaka, Atsushi;Okata, Shinichiro;Hashimoto, Hisayuki;Kusumoto, Dai;Kunitomi, Akira;Takei, Makoto;Kashimura, Shin;Suzuki, Tomoyuki;Yozu, Gakuto;Shimojima, Masaya;Motoda, Chikaaki;Hayashiji, Nozomi;Saito, Yuki;Goto, Yu-ichi;Fukuda, Keiichi
我们通过产生患者特异性iPS细胞来模拟线粒体疾病MELAS。MELAS-iPS细胞表现出多种异质性水平。具有高异质性水平的MELAS-iPS细胞显示受损的复合物I活性。线粒体疾病是由线粒体功能障碍引起的异质性疾病。线粒体不仅受核基因组DNA的调控，还受线粒体DNA的调控。由于缺乏线粒体疾病模型，很难开发有效的治疗线粒体疾病的方法。线粒体肌病、脑肌病、乳酸酸中毒和卒中样发作（MELAS）是主要的线粒体疾病之一。本研究的目的是产生MELAS特异性诱导多能干细胞（iPSC），并证明MELAS-iPSC可以作为线粒体疾病的模型。我们成功地从携带77.7%的m.3243A>G异质性的原代MELAS成纤维细胞建立了iPSC。MELAS-iPSC系的m. 3243 A>G异质性水平范围为3.6%至99.4%。线粒体呼吸复合物的酶活性表明，具有高异质性水平的MELAS-iPSC衍生的成纤维细胞显示复合物I活性的缺乏，但具有低异质性水平的MELAS-iPSC衍生的成纤维细胞显示正常的复合物I活性。我们的数据表明，MELAS-iPSC可以作为MELAS的模型，但我们应该仔细选择具有适当异质性水平和呼吸功能的MELAS-iPSC用于线粒体疾病建模。
We modeled the mitochondrial disease MELAS by generating patient-specific iPS cells. MELAS-iPS cells show a wide variety of heteroplasmy levels. MELAS-iPS cells with high heteroplasmy levels showed impaired complex I activity. Mitochondrial diseases are heterogeneous disorders, caused by mitochondrial dysfunction. Mitochondria are not regulated solely by nuclear genomic DNA but by mitochondrial DNA. It is difficult to develop effective therapies for mitochondrial disease because of the lack of mitochondrial disease models. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major mitochondrial diseases. The aim of this study was to generate MELAS-specific induced pluripotent stem cells (iPSCs) and to demonstrate that MELAS-iPSCs can be models for mitochondrial disease. We successfully established iPSCs from the primary MELAS-fibroblasts carrying 77.7% of m.3243A>G heteroplasmy. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.
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影响因子：
5.4
作者：
Tanaka A;Yuasa S;Mearini G;Egashira T;Seki T;Kodaira M;Kusumoto D;Kuroda Y;Okata S;Suzuki T;Inohara T;Arimura T;Makino S;Kimura K;Kimura A;Furukawa T;Carrier L;Node K;Fukuda K
通讯作者：
Fukuda K
DOI：
10.1038/nrg1606
发表时间：
2005-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
GOTO, Y;NONAKA, I;HORAI, S
通讯作者：
HORAI, S
影响因子：
11.2
作者：
Jeppesen, TD;Schwartz, M;Vissing, J
通讯作者：
Vissing, J
DOI：
10.1073/pnas.89.23.11164
发表时间：
1992-12-01
影响因子：
11.1
作者：
YONEDA, M;CHOMYN, A;ATTARDI, G
通讯作者：
ATTARDI, G