Impaired Respiratory Function in MELAS-induced Pluripotent Stem Cells with High Heteroplasmy Levels

Overview

Journal FEBS Open Bio

Specialty Biology

Date 2015 Apr 9

PMID 25853038

Citations 30

Authors

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

Affiliations

Soon will be listed here.

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.

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