Impaired respiratory function in MELAS‐induced pluripotent stem cells with high heteroplasmy levels

FEBS Open Bio

Hisayuki Hashimoto¹  Tomohisa Seki¹  Shugo Tohyama¹  Chikaaki Motoda¹  Akira Kunitomi¹  Atsushi Tanaka¹  Nozomi Hayashiji¹  Keiichi Fukuda¹  Shinichiro Okata¹  Dai Kusumoto¹  Makoto Takei¹  Yusuke Kuroda¹  Tomoyuki Suzuki¹  Masaya Shimojima¹  Masaki Kodaira¹  Yuki Saito¹  Shinsuke Yuasa¹  Toru Egashira¹  Shin Kashimura¹  Gakuto Yozu¹  Yu-ichi Goto²  Hideyuki Hatakeyama² 

[1] Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan;

关键词: MELAS;    iPS cell;    Mitochondrial disease;    Disease modeling;   

DOI  :  10.1016/j.fob.2015.03.008

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown