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Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease

Mitochondrial dysfunction is a major cytopathology in Huntington’s disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determi...

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Autores principales: Roe, Anne Jessica, Qi, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057844/
https://www.ncbi.nlm.nih.gov/pubmed/29397067
http://dx.doi.org/10.1016/j.bbrc.2018.01.114
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author Roe, Anne Jessica
Qi, Xin
author_facet Roe, Anne Jessica
Qi, Xin
author_sort Roe, Anne Jessica
collection PubMed
description Mitochondrial dysfunction is a major cytopathology in Huntington’s disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determine the role that Mitogen-activated protein kinase 1 (MAPK1) plays in the over-activation of Dynamin-related protein 1 (Drp1), the mitochondrial fission protein, which leads to mitochondrial dysfunction and neurodegeneration seen in HD. We show that MAPK1 binds to and phosphorylates Drp1 in vitro. Drp1 phosphorylation at serine 616 is increased in HD knock-in mouse derived striatal cells, which is abolished by treatment with U0126, a potent inhibitor of MEK1/2. A phosphorylation-deficient mutant of Drp1, Drp1S616A, corrects mitochondrial fragmentation associated with HD. Treatment with U0126 also reduces mitochondrial fragmentation, but has no additional effect in correcting aberrant mitochondrial morphology in cells expressing Drp1S616A. Finally, treatment with U0126 reduces mitochondrial depolarization and mitochondrial superoxide production in HD mutant striatal cells when compared to wildtype cells. This study suggests that in HD, MAPK1 activation leads to the aberrant mitochondrial fission and mitochondrial function by phosphorylating Drp1. Therefore, inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for development of therapy for treating HD.
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spelling pubmed-60578442019-01-01 Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease Roe, Anne Jessica Qi, Xin Biochem Biophys Res Commun Article Mitochondrial dysfunction is a major cytopathology in Huntington’s disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determine the role that Mitogen-activated protein kinase 1 (MAPK1) plays in the over-activation of Dynamin-related protein 1 (Drp1), the mitochondrial fission protein, which leads to mitochondrial dysfunction and neurodegeneration seen in HD. We show that MAPK1 binds to and phosphorylates Drp1 in vitro. Drp1 phosphorylation at serine 616 is increased in HD knock-in mouse derived striatal cells, which is abolished by treatment with U0126, a potent inhibitor of MEK1/2. A phosphorylation-deficient mutant of Drp1, Drp1S616A, corrects mitochondrial fragmentation associated with HD. Treatment with U0126 also reduces mitochondrial fragmentation, but has no additional effect in correcting aberrant mitochondrial morphology in cells expressing Drp1S616A. Finally, treatment with U0126 reduces mitochondrial depolarization and mitochondrial superoxide production in HD mutant striatal cells when compared to wildtype cells. This study suggests that in HD, MAPK1 activation leads to the aberrant mitochondrial fission and mitochondrial function by phosphorylating Drp1. Therefore, inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for development of therapy for treating HD. 2018-01-31 2018-02-05 /pmc/articles/PMC6057844/ /pubmed/29397067 http://dx.doi.org/10.1016/j.bbrc.2018.01.114 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Roe, Anne Jessica
Qi, Xin
Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title_full Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title_fullStr Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title_full_unstemmed Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title_short Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington’s disease
title_sort drp1 phosphorylation by mapk1 causes mitochondrial dysfunction in cell culture model of huntington’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057844/
https://www.ncbi.nlm.nih.gov/pubmed/29397067
http://dx.doi.org/10.1016/j.bbrc.2018.01.114
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