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Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs
Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affec...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386384/ https://www.ncbi.nlm.nih.gov/pubmed/28079893 http://dx.doi.org/10.1038/cddis.2016.484 |
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author | Yokota, Mutsumi Hatakeyama, Hideyuki Ono, Yasuha Kanazawa, Miyuki Goto, Yu-ichi |
author_facet | Yokota, Mutsumi Hatakeyama, Hideyuki Ono, Yasuha Kanazawa, Miyuki Goto, Yu-ichi |
author_sort | Yokota, Mutsumi |
collection | PubMed |
description | Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development. |
format | Online Article Text |
id | pubmed-5386384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53863842017-04-26 Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs Yokota, Mutsumi Hatakeyama, Hideyuki Ono, Yasuha Kanazawa, Miyuki Goto, Yu-ichi Cell Death Dis Original Article Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development. Nature Publishing Group 2017-01 2017-01-12 /pmc/articles/PMC5386384/ /pubmed/28079893 http://dx.doi.org/10.1038/cddis.2016.484 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Yokota, Mutsumi Hatakeyama, Hideyuki Ono, Yasuha Kanazawa, Miyuki Goto, Yu-ichi Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title | Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title_full | Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title_fullStr | Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title_full_unstemmed | Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title_short | Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs |
title_sort | mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human ipscs |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386384/ https://www.ncbi.nlm.nih.gov/pubmed/28079893 http://dx.doi.org/10.1038/cddis.2016.484 |
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