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Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells
BACKGROUND: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482938/ https://www.ncbi.nlm.nih.gov/pubmed/28646906 http://dx.doi.org/10.1186/s13287-017-0601-7 |
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author | Melcher, Marlen Danhauser, Katharina Seibt, Annette Degistirici, Özer Baertling, Fabian Kondadi, Arun Kumar Reichert, Andreas S. Koopman, Werner J. H. Willems, Peter H. G. M. Rodenburg, Richard J. Mayatepek, Ertan Meisel, Roland Distelmaier, Felix |
author_facet | Melcher, Marlen Danhauser, Katharina Seibt, Annette Degistirici, Özer Baertling, Fabian Kondadi, Arun Kumar Reichert, Andreas S. Koopman, Werner J. H. Willems, Peter H. G. M. Rodenburg, Richard J. Mayatepek, Ertan Meisel, Roland Distelmaier, Felix |
author_sort | Melcher, Marlen |
collection | PubMed |
description | BACKGROUND: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far available. The purpose of this study was to investigate whether and how mesenchymal stem cells (MSCs) are able to modulate metabolic function in fibroblast cell models of CI deficiency. METHODS: We used human and murine fibroblasts with a defect in the nuclear DNA encoded NDUFS4 subunit of CI. Fibroblasts were co-cultured with MSCs under different stress conditions and intercellular mitochondrial transfer was assessed by flow cytometry and fluorescence microscopy. Reactive oxygen species (ROS) levels were measured using MitoSOX-Red. Protein levels of CI were analysed by blue native polyacrylamide gel electrophoresis (BN-PAGE). RESULTS: Direct cellular interactions and mitochondrial transfer between MSCs and human as well as mouse fibroblast cell lines were demonstrated. Mitochondrial transfer was visible in 13.2% and 6% of fibroblasts (e.g. fibroblasts containing MSC mitochondria) for human and mouse cell lines, respectively. The transfer rate could be further stimulated via treatment of cells with TNF-α. MSCs effectively lowered cellular ROS production in NDUFS4-deficient fibroblast cell lines (either directly via co-culture or indirectly via incubation of cell lines with cell-free MSC supernatant). However, CI protein expression and activity were not rescued by MSC treatment. CONCLUSION: This study demonstrates the interplay between MSCs and fibroblast cell models of isolated CI deficiency including transfer of mitochondria as well as modulation of cellular ROS levels. Further exploration of these cellular interactions might help to develop MSC-based treatment strategies for human CI deficiency. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-017-0601-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5482938 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-54829382017-06-26 Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells Melcher, Marlen Danhauser, Katharina Seibt, Annette Degistirici, Özer Baertling, Fabian Kondadi, Arun Kumar Reichert, Andreas S. Koopman, Werner J. H. Willems, Peter H. G. M. Rodenburg, Richard J. Mayatepek, Ertan Meisel, Roland Distelmaier, Felix Stem Cell Res Ther Research BACKGROUND: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far available. The purpose of this study was to investigate whether and how mesenchymal stem cells (MSCs) are able to modulate metabolic function in fibroblast cell models of CI deficiency. METHODS: We used human and murine fibroblasts with a defect in the nuclear DNA encoded NDUFS4 subunit of CI. Fibroblasts were co-cultured with MSCs under different stress conditions and intercellular mitochondrial transfer was assessed by flow cytometry and fluorescence microscopy. Reactive oxygen species (ROS) levels were measured using MitoSOX-Red. Protein levels of CI were analysed by blue native polyacrylamide gel electrophoresis (BN-PAGE). RESULTS: Direct cellular interactions and mitochondrial transfer between MSCs and human as well as mouse fibroblast cell lines were demonstrated. Mitochondrial transfer was visible in 13.2% and 6% of fibroblasts (e.g. fibroblasts containing MSC mitochondria) for human and mouse cell lines, respectively. The transfer rate could be further stimulated via treatment of cells with TNF-α. MSCs effectively lowered cellular ROS production in NDUFS4-deficient fibroblast cell lines (either directly via co-culture or indirectly via incubation of cell lines with cell-free MSC supernatant). However, CI protein expression and activity were not rescued by MSC treatment. CONCLUSION: This study demonstrates the interplay between MSCs and fibroblast cell models of isolated CI deficiency including transfer of mitochondria as well as modulation of cellular ROS levels. Further exploration of these cellular interactions might help to develop MSC-based treatment strategies for human CI deficiency. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-017-0601-7) contains supplementary material, which is available to authorized users. BioMed Central 2017-06-24 /pmc/articles/PMC5482938/ /pubmed/28646906 http://dx.doi.org/10.1186/s13287-017-0601-7 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Melcher, Marlen Danhauser, Katharina Seibt, Annette Degistirici, Özer Baertling, Fabian Kondadi, Arun Kumar Reichert, Andreas S. Koopman, Werner J. H. Willems, Peter H. G. M. Rodenburg, Richard J. Mayatepek, Ertan Meisel, Roland Distelmaier, Felix Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title | Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title_full | Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title_fullStr | Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title_full_unstemmed | Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title_short | Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells |
title_sort | modulation of oxidative phosphorylation and redox homeostasis in mitochondrial ndufs4 deficiency via mesenchymal stem cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482938/ https://www.ncbi.nlm.nih.gov/pubmed/28646906 http://dx.doi.org/10.1186/s13287-017-0601-7 |
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