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Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury

Hypothermia (HT) is a standard of care in the management of hypoxic-ischemic brain injury (HI). However, therapeutic mechanisms of HT are not well understood. We found that at the temperature of 32°C, isolated brain mitochondria exhibited significantly greater resistance to an opening of calcium-ind...

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Autores principales: Sosunov, Sergey, Bhutada, Arnav, Niatsetskaya, Zoya, Starkov, Anatoly, Ten, Vadim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9432759/
https://www.ncbi.nlm.nih.gov/pubmed/36044480
http://dx.doi.org/10.1371/journal.pone.0273677
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author Sosunov, Sergey
Bhutada, Arnav
Niatsetskaya, Zoya
Starkov, Anatoly
Ten, Vadim
author_facet Sosunov, Sergey
Bhutada, Arnav
Niatsetskaya, Zoya
Starkov, Anatoly
Ten, Vadim
author_sort Sosunov, Sergey
collection PubMed
description Hypothermia (HT) is a standard of care in the management of hypoxic-ischemic brain injury (HI). However, therapeutic mechanisms of HT are not well understood. We found that at the temperature of 32°C, isolated brain mitochondria exhibited significantly greater resistance to an opening of calcium-induced permeability transition pore (mPTP), compared to 37°C. Mitochondrial calcium buffering capacity (mCBC) was linearly and inversely dependent upon temperature (25°C—37°C). Importantly, at 37°C cyclosporine A did not increase mCBC, but significantly increased mCBC at lower temperature. Because mPTP contributes to reperfusion injury, we hypothesized that HT protects brain by improvement of mitochondrial tolerance to mPTP activation. Immediately after HI-insult, isolated brain mitochondria demonstrated very poor mCBC. At 30 minutes of reperfusion, in mice recovered under normothermia (NT) or HT, mCBC significantly improved. However, at four hours of reperfusion, only NT mice exhibited secondary decline of mCBC. HT-mice maintained their recovered mCBC and this was associated with significant neuroprotection. Direct inverted dependence of mCBC upon temperature in vitro and significantly increased mitochondrial resistance to mPTP activation after therapeutic HT ex vivo suggest that hypothermia-driven inhibition of calcium-induced mitochondrial mPTP activation mechanistically contributes to the neuroprotection associated with hypothermia.
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spelling pubmed-94327592022-09-01 Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury Sosunov, Sergey Bhutada, Arnav Niatsetskaya, Zoya Starkov, Anatoly Ten, Vadim PLoS One Research Article Hypothermia (HT) is a standard of care in the management of hypoxic-ischemic brain injury (HI). However, therapeutic mechanisms of HT are not well understood. We found that at the temperature of 32°C, isolated brain mitochondria exhibited significantly greater resistance to an opening of calcium-induced permeability transition pore (mPTP), compared to 37°C. Mitochondrial calcium buffering capacity (mCBC) was linearly and inversely dependent upon temperature (25°C—37°C). Importantly, at 37°C cyclosporine A did not increase mCBC, but significantly increased mCBC at lower temperature. Because mPTP contributes to reperfusion injury, we hypothesized that HT protects brain by improvement of mitochondrial tolerance to mPTP activation. Immediately after HI-insult, isolated brain mitochondria demonstrated very poor mCBC. At 30 minutes of reperfusion, in mice recovered under normothermia (NT) or HT, mCBC significantly improved. However, at four hours of reperfusion, only NT mice exhibited secondary decline of mCBC. HT-mice maintained their recovered mCBC and this was associated with significant neuroprotection. Direct inverted dependence of mCBC upon temperature in vitro and significantly increased mitochondrial resistance to mPTP activation after therapeutic HT ex vivo suggest that hypothermia-driven inhibition of calcium-induced mitochondrial mPTP activation mechanistically contributes to the neuroprotection associated with hypothermia. Public Library of Science 2022-08-31 /pmc/articles/PMC9432759/ /pubmed/36044480 http://dx.doi.org/10.1371/journal.pone.0273677 Text en © 2022 Sosunov et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sosunov, Sergey
Bhutada, Arnav
Niatsetskaya, Zoya
Starkov, Anatoly
Ten, Vadim
Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title_full Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title_fullStr Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title_full_unstemmed Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title_short Mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
title_sort mitochondrial calcium buffering depends upon temperature and is associated with hypothermic neuroprotection against hypoxia-ischemia injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9432759/
https://www.ncbi.nlm.nih.gov/pubmed/36044480
http://dx.doi.org/10.1371/journal.pone.0273677
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