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Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition.

Hansson, Magnus LU ; Månsson, Roland LU ; Morota, Saori LU ; Uchino, Hiroyuki; Kallur, Therese LU ; Sumi, Tetsuo; Ishii, Nagao; Shimazu, Motohide; Keep, Marcus F and Jegorov, Alexandr, et al. (2008) In Free Radical Biology & Medicine 45. p.284-294
Abstract
Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was... (More)
Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH- and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death. (Less)
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published
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Free Radical Biology & Medicine
volume
45
pages
284 - 294
publisher
Elsevier
external identifiers
  • wos:000257089300007
  • pmid:18466779
  • scopus:46449116985
ISSN
0891-5849
DOI
10.1016/j.freeradbiomed.2008.04.021
language
English
LU publication?
yes
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3647ee34-b127-48ca-9197-98134ee0e5c2 (old id 1154373)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18466779?dopt=Abstract
date added to LUP
2008-06-03 11:04:58
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2017-11-19 04:16:11
@article{3647ee34-b127-48ca-9197-98134ee0e5c2,
  abstract     = {Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH- and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.},
  author       = {Hansson, Magnus and Månsson, Roland and Morota, Saori and Uchino, Hiroyuki and Kallur, Therese and Sumi, Tetsuo and Ishii, Nagao and Shimazu, Motohide and Keep, Marcus F and Jegorov, Alexandr and Elmer, Eskil},
  issn         = {0891-5849},
  language     = {eng},
  pages        = {284--294},
  publisher    = {Elsevier},
  series       = {Free Radical Biology & Medicine},
  title        = {Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition.},
  url          = {http://dx.doi.org/10.1016/j.freeradbiomed.2008.04.021},
  volume       = {45},
  year         = {2008},
}