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 Saito; Yu ichi Goto; Keiichi Fukuda

doi:10.1016/j.fob.2015.03.008

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 journal › Article › peer-review

52 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 language	English
Pages (from-to)	219-225
Number of pages	7
Journal	FEBS Open Bio
Volume	5
DOIs	https://doi.org/10.1016/j.fob.2015.03.008
Publication status	Published - 01-04-2015
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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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

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title = "Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = apr,

day = "1",

doi = "10.1016/j.fob.2015.03.008",

language = "English",

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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, Saito, Y, Goto, YI & Fukuda, K 2015, 'Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels', FEBS Open Bio, vol. 5, pp. 219-225. https://doi.org/10.1016/j.fob.2015.03.008

TY - JOUR

T1 - Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels

AU - Kodaira, Masaki

AU - Hatakeyama, Hideyuki

AU - Yuasa, Shinsuke

AU - Seki, Tomohisa

AU - Egashira, Toru

AU - Tohyama, Shugo

AU - Kuroda, Yusuke

AU - Tanaka, Atsushi

AU - Okata, Shinichiro

AU - Hashimoto, Hisayuki

AU - Kusumoto, Dai

AU - Kunitomi, Akira

AU - Takei, Makoto

AU - Kashimura, Shin

AU - Suzuki, Tomoyuki

AU - Yozu, Gakuto

AU - Shimojima, Masaya

AU - Motoda, Chikaaki

AU - Hayashiji, Nozomi

AU - Saito, Yuki

AU - Goto, Yu ichi

AU - Fukuda, Keiichi

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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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DO - 10.1016/j.fob.2015.03.008

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EP - 225

JO - FEBS Open Bio

JF - FEBS Open Bio

ER -

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

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