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Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo

Mitochondria form a dynamic network governed by a balance between opposing fission and fusion processes. Because excessive mitochondrial fission correlates with numerous pathologies, including neurodegeneration, the mechanism governing fission has become an attractive therapeutic strategy. However,...

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Autores principales: Kornfeld, Opher S., Qvit, Nir, Haileselassie, Bereketeab, Shamloo, Mehrdad, Bernardi, Paolo, Mochly-Rosen, Daria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145916/
https://www.ncbi.nlm.nih.gov/pubmed/30232469
http://dx.doi.org/10.1038/s41598-018-32228-1
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author Kornfeld, Opher S.
Qvit, Nir
Haileselassie, Bereketeab
Shamloo, Mehrdad
Bernardi, Paolo
Mochly-Rosen, Daria
author_facet Kornfeld, Opher S.
Qvit, Nir
Haileselassie, Bereketeab
Shamloo, Mehrdad
Bernardi, Paolo
Mochly-Rosen, Daria
author_sort Kornfeld, Opher S.
collection PubMed
description Mitochondria form a dynamic network governed by a balance between opposing fission and fusion processes. Because excessive mitochondrial fission correlates with numerous pathologies, including neurodegeneration, the mechanism governing fission has become an attractive therapeutic strategy. However, targeting fission is a double-edged sword as physiological fission is necessary for mitochondrial function. Fission is trigged by Drp1 anchoring to adaptors tethered to the outer mitochondrial membrane. We designed peptide P259 that distinguishes physiological from pathological fission by specifically inhibiting Drp1′s interaction with the Mff adaptor. Treatment of cells with P259 elongated mitochondria and disrupted mitochondrial function and motility. Sustained in vivo treatment caused a decline in ATP levels and altered mitochondrial structure in the brain, resulting in behavioral deficits in wild-type mice and a shorter lifespan in a mouse model of Huntington’s disease. Therefore, the Mff-Drp1 interaction is critical for physiological mitochondrial fission, motility, and function in vitro and in vivo. Tools, such as P259, that differentiate physiological from pathological fission will enable the examination of context-dependent roles of Drp1 and the suitability of mitochondrial fission as a target for drug development.
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spelling pubmed-61459162018-09-24 Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo Kornfeld, Opher S. Qvit, Nir Haileselassie, Bereketeab Shamloo, Mehrdad Bernardi, Paolo Mochly-Rosen, Daria Sci Rep Article Mitochondria form a dynamic network governed by a balance between opposing fission and fusion processes. Because excessive mitochondrial fission correlates with numerous pathologies, including neurodegeneration, the mechanism governing fission has become an attractive therapeutic strategy. However, targeting fission is a double-edged sword as physiological fission is necessary for mitochondrial function. Fission is trigged by Drp1 anchoring to adaptors tethered to the outer mitochondrial membrane. We designed peptide P259 that distinguishes physiological from pathological fission by specifically inhibiting Drp1′s interaction with the Mff adaptor. Treatment of cells with P259 elongated mitochondria and disrupted mitochondrial function and motility. Sustained in vivo treatment caused a decline in ATP levels and altered mitochondrial structure in the brain, resulting in behavioral deficits in wild-type mice and a shorter lifespan in a mouse model of Huntington’s disease. Therefore, the Mff-Drp1 interaction is critical for physiological mitochondrial fission, motility, and function in vitro and in vivo. Tools, such as P259, that differentiate physiological from pathological fission will enable the examination of context-dependent roles of Drp1 and the suitability of mitochondrial fission as a target for drug development. Nature Publishing Group UK 2018-09-19 /pmc/articles/PMC6145916/ /pubmed/30232469 http://dx.doi.org/10.1038/s41598-018-32228-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kornfeld, Opher S.
Qvit, Nir
Haileselassie, Bereketeab
Shamloo, Mehrdad
Bernardi, Paolo
Mochly-Rosen, Daria
Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title_full Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title_fullStr Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title_full_unstemmed Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title_short Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
title_sort interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145916/
https://www.ncbi.nlm.nih.gov/pubmed/30232469
http://dx.doi.org/10.1038/s41598-018-32228-1
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