title: Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels.
abstract: 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.
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Masaki
authors: M
authors: Kodaira
authors: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan ; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors: Hideyuki
authors: H
authors: Hatakeyama
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Shinsuke
authors: S
authors: Yuasa
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Tomohisa
authors: T
authors: Seki
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Toru
authors: T
authors: Egashira
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Shugo
authors: S
authors: Tohyama
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Yusuke
authors: Y
authors: Kuroda
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Tanaka
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Shinichiro
authors: S
authors: Okata
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Hisayuki
authors: H
authors: Hashimoto
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Dai
authors: D
authors: Kusumoto
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Akira
authors: A
authors: Kunitomi
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Makoto
authors: M
authors: Takei
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Shin
authors: S
authors: Kashimura
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Tomoyuki
authors: T
authors: Suzuki
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Gakuto
authors: G
authors: Yozu
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Masaya
authors: M
authors: Shimojima
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Chikaaki
authors: C
authors: Motoda
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Nozomi
authors: N
authors: Hayashiji
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Yuki
authors: Y
authors: Saito
authors: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan ; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors: Yu-Ichi
authors: Y
authors: Goto
authors: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors: Keiichi
authors: K
authors: Fukuda
keywords: Disease modeling; EB, embryoid body; ES, embryonic stem; KSR, Knock-out Serum Replacement; MEF, mouse embryonic fibroblast; MELAS; MELAS, mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes; Mitochondrial disease; OXPHOS, oxidative phosphorylation system; bFGF, basic fibroblast growth factor; iPS cell; iPSCs, induced pluripotent stem cells; mtDNA, mitochondrial DNA