Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria

The objective of the present study was to validate the presence and explore the characteristics of mitochondrial permeability transition (mPT) in isolated mitochondria from human heart tissue in order to investigate if previous findings in animal models of cardiac disorders are translatable to human...

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Main Authors:	Morota, Saori, Manolopoulos, Theodor, Eyjolfsson, Atli, Kimblad, Per-Ola, Wierup, Per, Metzsch, Carsten, Blomquist, Sten, Hansson, Magnus J.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695980/

id	pubmed-3695980
recordtype	oai_dc
spelling	pubmed-36959802013-07-09 Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria Morota, Saori Manolopoulos, Theodor Eyjolfsson, Atli Kimblad, Per-Ola Wierup, Per Metzsch, Carsten Blomquist, Sten Hansson, Magnus J. Research Article The objective of the present study was to validate the presence and explore the characteristics of mitochondrial permeability transition (mPT) in isolated mitochondria from human heart tissue in order to investigate if previous findings in animal models of cardiac disorders are translatable to human disease. Mitochondria were rapidly isolated from fresh atrial tissue samples obtained from 14 patients undergoing Maze surgery due to atrial fibrillation. Human heart mitochondria exhibited typical mPT characteristics upon calcium overload such as swelling, evaluated by changes in light scattering, inhibition of respiration and loss of respiratory coupling. Swelling was a morphologically reversible event following transient calcium challenge. Calcium retention capacity (CRC), a quantitative measure of mPT sensitivity assayed by following extramitochondrial [Ca2+] and changes in respiration during a continuous calcium infusion, was significantly increased by cyclophilin D (CypD) inhibitors. The thiol-reactive oxidant phenylarsine oxide sensitized mitochondria to calcium-induced mPT. Release of the pro-apoptotic intermembrane protein cytochrome c was increased after, but not before, calcium discharge and respiratory inhibition in the CRC assay. From the present study, we conclude that adult viable heart mitochondria have a CypD- and oxidant-regulated mPT. The findings support that inhibition of mPT may be a relevant pharmacological target in human cardiac disease and may underlie the beneficial effect of cyclosporin A in reperfusion injury. Public Library of Science 2013-06-28 /pmc/articles/PMC3695980/ /pubmed/23840770 http://dx.doi.org/10.1371/journal.pone.0067747 Text en © 2013 Morota 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Morota, Saori Manolopoulos, Theodor Eyjolfsson, Atli Kimblad, Per-Ola Wierup, Per Metzsch, Carsten Blomquist, Sten Hansson, Magnus J.
spellingShingle	Morota, Saori Manolopoulos, Theodor Eyjolfsson, Atli Kimblad, Per-Ola Wierup, Per Metzsch, Carsten Blomquist, Sten Hansson, Magnus J. Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
author_facet	Morota, Saori Manolopoulos, Theodor Eyjolfsson, Atli Kimblad, Per-Ola Wierup, Per Metzsch, Carsten Blomquist, Sten Hansson, Magnus J.
author_sort	Morota, Saori
title	Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
title_short	Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
title_full	Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
title_fullStr	Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
title_full_unstemmed	Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria
title_sort	functional and pharmacological characteristics of permeability transition in isolated human heart mitochondria
description	The objective of the present study was to validate the presence and explore the characteristics of mitochondrial permeability transition (mPT) in isolated mitochondria from human heart tissue in order to investigate if previous findings in animal models of cardiac disorders are translatable to human disease. Mitochondria were rapidly isolated from fresh atrial tissue samples obtained from 14 patients undergoing Maze surgery due to atrial fibrillation. Human heart mitochondria exhibited typical mPT characteristics upon calcium overload such as swelling, evaluated by changes in light scattering, inhibition of respiration and loss of respiratory coupling. Swelling was a morphologically reversible event following transient calcium challenge. Calcium retention capacity (CRC), a quantitative measure of mPT sensitivity assayed by following extramitochondrial [Ca2+] and changes in respiration during a continuous calcium infusion, was significantly increased by cyclophilin D (CypD) inhibitors. The thiol-reactive oxidant phenylarsine oxide sensitized mitochondria to calcium-induced mPT. Release of the pro-apoptotic intermembrane protein cytochrome c was increased after, but not before, calcium discharge and respiratory inhibition in the CRC assay. From the present study, we conclude that adult viable heart mitochondria have a CypD- and oxidant-regulated mPT. The findings support that inhibition of mPT may be a relevant pharmacological target in human cardiac disease and may underlie the beneficial effect of cyclosporin A in reperfusion injury.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695980/
_version_	1611990437660196864

Functional and Pharmacological Characteristics of Permeability Transition in Isolated Human Heart Mitochondria

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