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

Masaki Kodaira, Hideyuki Hatakeyama, Shinsuke Yuasa, Tomohisa Seki, Toru Egashira, Shugo Tohyama, Yusuke Kuroda, Atsushi Tanaka, Shinichiro Okata, Hisayuki Hashimoto, Dai Kusumoto, Akira Kunitomi, Makoto Takei, Shin Kashimura, Tomoyuki Suzuki, Gakuto Yozu, Masaya Shimojima, Chikaaki Motoda, Nozomi Hayashiji, Yuki SaitoYu ichi Goto, Keiichi Fukuda

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)219-225
Number of pages7
JournalFEBS Open Bio
Volume5
DOIs
Publication statusPublished - 2015 Apr 1

Keywords

  • Disease modeling
  • IPS cell
  • MELAS
  • Mitochondrial disease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kodaira, M., Hatakeyama, H., Yuasa, S., Seki, T., Egashira, T., Tohyama, S., Kuroda, Y., Tanaka, A., Okata, S., Hashimoto, H., Kusumoto, D., Kunitomi, A., Takei, M., Kashimura, S., Suzuki, T., Yozu, G., Shimojima, M., Motoda, C., Hayashiji, N., ... Fukuda, K. (2015). Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels. FEBS Open Bio, 5, 219-225. https://doi.org/10.1016/j.fob.2015.03.008