Advanced

Functional and pharmacological characteristics of permeability transition in isolated human heart mitochondria.

Morota, Saori LU ; Manolopoulos, Theodor; Eyjolfsson, Atli LU ; Kimblad, Per Ola LU ; Wierup, Per LU ; Metzsch, Carsten LU ; Blomquist, Sten LU and Hansson, Magnus LU (2013) In PLoS ONE 8(6).
Abstract
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.... (More)
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 [Ca(2+)] 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
8
issue
6
publisher
Public Library of Science
external identifiers
  • wos:000321148400131
  • pmid:23840770
  • scopus:84879546452
ISSN
1932-6203
DOI
10.1371/journal.pone.0067747
language
English
LU publication?
yes
id
dd3dc9f9-e4eb-4adc-a174-5949053a0a33 (old id 3956020)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23840770?dopt=Abstract
date added to LUP
2013-08-02 11:51:14
date last changed
2019-03-05 02:15:21
@article{dd3dc9f9-e4eb-4adc-a174-5949053a0a33,
  abstract     = {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 [Ca(2+)] 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.},
  articleno    = {e67747},
  author       = {Morota, Saori and Manolopoulos, Theodor and Eyjolfsson, Atli and Kimblad, Per Ola and Wierup, Per and Metzsch, Carsten and Blomquist, Sten and Hansson, Magnus},
  issn         = {1932-6203},
  language     = {eng},
  number       = {6},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Functional and pharmacological characteristics of permeability transition in isolated human heart mitochondria.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0067747},
  volume       = {8},
  year         = {2013},
}