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SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling
Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca(2+)) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linka...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964177/ https://www.ncbi.nlm.nih.gov/pubmed/29789578 http://dx.doi.org/10.1038/s41419-018-0590-1 |
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author | Honrath, Birgit Krabbendam, Inge E. IJsebaart, Carmen Pegoretti, Valentina Bendridi, Nadia Rieusset, Jennifer Schmidt, Martina Culmsee, Carsten Dolga, Amalia M. |
author_facet | Honrath, Birgit Krabbendam, Inge E. IJsebaart, Carmen Pegoretti, Valentina Bendridi, Nadia Rieusset, Jennifer Schmidt, Martina Culmsee, Carsten Dolga, Amalia M. |
author_sort | Honrath, Birgit |
collection | PubMed |
description | Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca(2+)) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linkage may reduce Ca(2+) uptake into mitochondria, while fortifying these organelle contact sites may promote mitochondrial Ca(2+) overload and cell death. Small conductance Ca(2+)-activated K(+) (SK) channels regulate mitochondrial respiration, and their activation attenuates mitochondrial damage in paradigms of oxidative stress. In the present study, we enhanced ER–mitochondrial coupling and investigated the impact of SK channels on survival of neuronal HT22 cells in conditions of oxidative stress. Using genetically encoded linkers, we show that mitochondrial respiration and the vulnerability of neuronal cells to oxidative stress was inversely linked to the strength of ER–mitochondrial contact points and the increase in mitochondrial Ca(2+) uptake. Pharmacological activation of SK channels provided protection against glutamate-induced cell death and also in conditions of increased ER–mitochondrial coupling. Together, this study revealed that SK channel activation provided persistent neuroprotection in the paradigm of glutamate-induced oxytosis even in conditions where an increase in ER–mitochondrial coupling potentiated mitochondrial Ca(2+) influx and impaired mitochondrial bioenergetics. |
format | Online Article Text |
id | pubmed-5964177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59641772018-05-24 SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling Honrath, Birgit Krabbendam, Inge E. IJsebaart, Carmen Pegoretti, Valentina Bendridi, Nadia Rieusset, Jennifer Schmidt, Martina Culmsee, Carsten Dolga, Amalia M. Cell Death Dis Article Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca(2+)) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linkage may reduce Ca(2+) uptake into mitochondria, while fortifying these organelle contact sites may promote mitochondrial Ca(2+) overload and cell death. Small conductance Ca(2+)-activated K(+) (SK) channels regulate mitochondrial respiration, and their activation attenuates mitochondrial damage in paradigms of oxidative stress. In the present study, we enhanced ER–mitochondrial coupling and investigated the impact of SK channels on survival of neuronal HT22 cells in conditions of oxidative stress. Using genetically encoded linkers, we show that mitochondrial respiration and the vulnerability of neuronal cells to oxidative stress was inversely linked to the strength of ER–mitochondrial contact points and the increase in mitochondrial Ca(2+) uptake. Pharmacological activation of SK channels provided protection against glutamate-induced cell death and also in conditions of increased ER–mitochondrial coupling. Together, this study revealed that SK channel activation provided persistent neuroprotection in the paradigm of glutamate-induced oxytosis even in conditions where an increase in ER–mitochondrial coupling potentiated mitochondrial Ca(2+) influx and impaired mitochondrial bioenergetics. Nature Publishing Group UK 2018-05-22 /pmc/articles/PMC5964177/ /pubmed/29789578 http://dx.doi.org/10.1038/s41419-018-0590-1 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 Honrath, Birgit Krabbendam, Inge E. IJsebaart, Carmen Pegoretti, Valentina Bendridi, Nadia Rieusset, Jennifer Schmidt, Martina Culmsee, Carsten Dolga, Amalia M. SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title | SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title_full | SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title_fullStr | SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title_full_unstemmed | SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title_short | SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling |
title_sort | sk channel activation is neuroprotective in conditions of enhanced er–mitochondrial coupling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964177/ https://www.ncbi.nlm.nih.gov/pubmed/29789578 http://dx.doi.org/10.1038/s41419-018-0590-1 |
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