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Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats

Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. How...

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Autores principales: Thompson, John W., Dave, Kunjan R., Saul, Isabel, Narayanan, Srinivasan V., Perez-Pinzon, Miguel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772907/
https://www.ncbi.nlm.nih.gov/pubmed/24058702
http://dx.doi.org/10.1371/journal.pone.0075753
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author Thompson, John W.
Dave, Kunjan R.
Saul, Isabel
Narayanan, Srinivasan V.
Perez-Pinzon, Miguel A.
author_facet Thompson, John W.
Dave, Kunjan R.
Saul, Isabel
Narayanan, Srinivasan V.
Perez-Pinzon, Miguel A.
author_sort Thompson, John W.
collection PubMed
description Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. However, a recent study demonstrated that SIRT1 can also localize to the mitochondria. Mitochondrial localized SIRT1 may allow for a direct protection of mitochondria following ischemic preconditioning. The objective of this study was to determine whether ischemic preconditioning increases brain mitochondrial SIRT1 protein levels and to determine the role of PKCɛ and HSP90 in targeting SIRT1 to the mitochondria. Here we report that preconditioning rats, with 2 min of global cerebral ischemia, induces a delayed increase in non-synaptic mitochondrial SIRT1 protein levels which was not observed in synaptic mitochondria. This increase in mitochondrial SIRT1 protein was found to occur only in neuronal cells and was mediated by PKCε activation. Inhibition of HSP90, a protein chaperone involved in mitochondrial protein import, prevented preconditioning induced increases in mitochondrial SIRT1 and PKCε protein. Our work provides new insights into a possible direct role of SIRT1 in modulating mitochondrial function under both normal and stress conditions, and to a possible role of mitochondrial SIRT1 in activating preconditioning induced ischemic tolerance.
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spelling pubmed-37729072013-09-20 Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats Thompson, John W. Dave, Kunjan R. Saul, Isabel Narayanan, Srinivasan V. Perez-Pinzon, Miguel A. PLoS One Research Article Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. However, a recent study demonstrated that SIRT1 can also localize to the mitochondria. Mitochondrial localized SIRT1 may allow for a direct protection of mitochondria following ischemic preconditioning. The objective of this study was to determine whether ischemic preconditioning increases brain mitochondrial SIRT1 protein levels and to determine the role of PKCɛ and HSP90 in targeting SIRT1 to the mitochondria. Here we report that preconditioning rats, with 2 min of global cerebral ischemia, induces a delayed increase in non-synaptic mitochondrial SIRT1 protein levels which was not observed in synaptic mitochondria. This increase in mitochondrial SIRT1 protein was found to occur only in neuronal cells and was mediated by PKCε activation. Inhibition of HSP90, a protein chaperone involved in mitochondrial protein import, prevented preconditioning induced increases in mitochondrial SIRT1 and PKCε protein. Our work provides new insights into a possible direct role of SIRT1 in modulating mitochondrial function under both normal and stress conditions, and to a possible role of mitochondrial SIRT1 in activating preconditioning induced ischemic tolerance. Public Library of Science 2013-09-13 /pmc/articles/PMC3772907/ /pubmed/24058702 http://dx.doi.org/10.1371/journal.pone.0075753 Text en © 2013 Thompson et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Thompson, John W.
Dave, Kunjan R.
Saul, Isabel
Narayanan, Srinivasan V.
Perez-Pinzon, Miguel A.
Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title_full Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title_fullStr Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title_full_unstemmed Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title_short Epsilon PKC Increases Brain Mitochondrial SIRT1 Protein Levels via Heat Shock Protein 90 following Ischemic Preconditioning in Rats
title_sort epsilon pkc increases brain mitochondrial sirt1 protein levels via heat shock protein 90 following ischemic preconditioning in rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772907/
https://www.ncbi.nlm.nih.gov/pubmed/24058702
http://dx.doi.org/10.1371/journal.pone.0075753
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