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Respiratory uncoupling by increased H+ or K+ flux is beneficial for heart mitochondrial turnover of reactive oxygen species but not for permeability transition

Morota, Saori LU ; Piel, Sarah LU and Hansson, Magnus LU (2013) In BMC Cell Biology 14.
Abstract
Background: Ischemic preconditioning has been proposed to involve changes in mitochondrial H+ and K+ fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K+ channels (MitoK(ATP)). The objectives of the present study were to explore how increased H+ and K+ fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). Results: Isolated rat heart mitochondria were exposed to a wide concentration range of the protonophore CCCP or the potassium ionophore valinomycin to induce increased H+ and K+ conductance, respectively. Simultaneous monitoring of mitochondrial... (More)
Background: Ischemic preconditioning has been proposed to involve changes in mitochondrial H+ and K+ fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K+ channels (MitoK(ATP)). The objectives of the present study were to explore how increased H+ and K+ fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). Results: Isolated rat heart mitochondria were exposed to a wide concentration range of the protonophore CCCP or the potassium ionophore valinomycin to induce increased H+ and K+ conductance, respectively. Simultaneous monitoring of mitochondrial respiration and calcium retention capacity (CRC) demonstrated that the relative increase in respiration caused by valinomycin or CCCP correlated with a decrease in CRC, and that no level of respiratory uncoupling was associated with enhanced resistance to mPT. Mitochondria suspended in hyperosmolar buffer demonstrated a dose-dependent reduction in CRC with increasing osmolarity. However, mitochondria in hypoosmolar buffer to increase matrix volume did not display increased CRC. ROS generation was reduced by both K+- and H+-mediated respiratory uncoupling. The ability of heart mitochondria to detoxify H2O2 was substantially greater than the production rate. The H2O2 detoxification was dependent on respiratory substrates and was dramatically decreased following calcium-induced mPT, but was unaffected by uncoupling via increased K+ and H+ conductance. Conclusion: It is concluded that respiratory uncoupling is not directly beneficial to rat heart mitochondrial resistance to calcium overload irrespective of whether H+ or K+ conductance is increased. The negative effects of respiratory uncoupling thus probably outweigh the reduction in ROS generation and a potential positive effect by increased matrix volume, resulting in a net sensitization of heart mitochondria to mPT activation. (Less)
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author
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type
Contribution to journal
publication status
published
subject
keywords
Ischemic preconditioning, Mitochondrial permeability transition, Potassium channels, Respiratory uncoupling, Reactive oxygen species
in
BMC Cell Biology
volume
14
article number
40
publisher
BioMed Central (BMC)
external identifiers
  • wos:000325083200001
  • scopus:84884323953
  • pmid:24053891
ISSN
1471-2121
DOI
10.1186/1471-2121-14-40
language
English
LU publication?
yes
id
0291e30f-db60-4228-8296-9444900e444d (old id 4172547)
date added to LUP
2016-04-01 14:36:42
date last changed
2020-01-12 16:35:52
@article{0291e30f-db60-4228-8296-9444900e444d,
  abstract     = {Background: Ischemic preconditioning has been proposed to involve changes in mitochondrial H+ and K+ fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K+ channels (MitoK(ATP)). The objectives of the present study were to explore how increased H+ and K+ fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). Results: Isolated rat heart mitochondria were exposed to a wide concentration range of the protonophore CCCP or the potassium ionophore valinomycin to induce increased H+ and K+ conductance, respectively. Simultaneous monitoring of mitochondrial respiration and calcium retention capacity (CRC) demonstrated that the relative increase in respiration caused by valinomycin or CCCP correlated with a decrease in CRC, and that no level of respiratory uncoupling was associated with enhanced resistance to mPT. Mitochondria suspended in hyperosmolar buffer demonstrated a dose-dependent reduction in CRC with increasing osmolarity. However, mitochondria in hypoosmolar buffer to increase matrix volume did not display increased CRC. ROS generation was reduced by both K+- and H+-mediated respiratory uncoupling. The ability of heart mitochondria to detoxify H2O2 was substantially greater than the production rate. The H2O2 detoxification was dependent on respiratory substrates and was dramatically decreased following calcium-induced mPT, but was unaffected by uncoupling via increased K+ and H+ conductance. Conclusion: It is concluded that respiratory uncoupling is not directly beneficial to rat heart mitochondrial resistance to calcium overload irrespective of whether H+ or K+ conductance is increased. The negative effects of respiratory uncoupling thus probably outweigh the reduction in ROS generation and a potential positive effect by increased matrix volume, resulting in a net sensitization of heart mitochondria to mPT activation.},
  author       = {Morota, Saori and Piel, Sarah and Hansson, Magnus},
  issn         = {1471-2121},
  language     = {eng},
  publisher    = {BioMed Central (BMC)},
  series       = {BMC Cell Biology},
  title        = {Respiratory uncoupling by increased H+ or K+ flux is beneficial for heart mitochondrial turnover of reactive oxygen species but not for permeability transition},
  url          = {https://lup.lub.lu.se/search/ws/files/4067673/4610157.pdf},
  doi          = {10.1186/1471-2121-14-40},
  volume       = {14},
  year         = {2013},
}