TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation

Naoki Yahata, Yuji Matsumoto, Minoru Omi, Naoki Yamamoto, Ryuji Hata

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Induced pluripotent stem cells (iPSCs) are suitable for studying mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations. Here, we generated iPSCs from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with the m.13513G>A mutation. The patient's dermal fibroblasts were reprogrammed, and we established two iPSC clones with and without mutant mtDNA. Furthermore, we tried to decrease mutant mtDNA level in iPSCs using transcription activator-like effector nucleases (TALENs). We originally engineered platinum TALENs, which were transported into mitochondria, recognized the mtDNA sequence including the m.13513 position, and preferentially cleaved G13513A mutant mtDNA (G13513A-mpTALEN). The m.13513G>A heteroplasmy level in MELAS-iPSCs was decreased in the short term by transduction of G13513A-mpTALEN. Our data demonstrate that this mtDNA-targeted nuclease would be a powerful tool for changing the heteroplasmy level in heteroplasmic iPSCs, which could contribute to elucidation of the pathological mechanisms of mitochondrial diseases caused by mtDNA mutations.

Original languageEnglish
Article number15557
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 01-12-2017

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Induced Pluripotent Stem Cells
Lactic Acidosis
Brain Diseases
Muscular Diseases
Mitochondrial DNA
Stroke
Mutation
Mitochondrial Diseases
MELAS Syndrome
Deoxyribonucleases
Transcription Activator-Like Effector Nucleases
Platinum
Mitochondria
Clone Cells
Fibroblasts
Skin

All Science Journal Classification (ASJC) codes

  • General

Cite this

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abstract = "Induced pluripotent stem cells (iPSCs) are suitable for studying mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations. Here, we generated iPSCs from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with the m.13513G>A mutation. The patient's dermal fibroblasts were reprogrammed, and we established two iPSC clones with and without mutant mtDNA. Furthermore, we tried to decrease mutant mtDNA level in iPSCs using transcription activator-like effector nucleases (TALENs). We originally engineered platinum TALENs, which were transported into mitochondria, recognized the mtDNA sequence including the m.13513 position, and preferentially cleaved G13513A mutant mtDNA (G13513A-mpTALEN). The m.13513G>A heteroplasmy level in MELAS-iPSCs was decreased in the short term by transduction of G13513A-mpTALEN. Our data demonstrate that this mtDNA-targeted nuclease would be a powerful tool for changing the heteroplasmy level in heteroplasmic iPSCs, which could contribute to elucidation of the pathological mechanisms of mitochondrial diseases caused by mtDNA mutations.",
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TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation. / Yahata, Naoki; Matsumoto, Yuji; Omi, Minoru; Yamamoto, Naoki; Hata, Ryuji.

In: Scientific Reports, Vol. 7, No. 1, 15557, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Hata, Ryuji

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