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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Magnus Hansson
  • Roland Månsson
  • Saori Morota
  • Hiroyuki Uchino
  • Therese Kallur
  • Tetsuo Sumi
  • Nagao Ishii
  • Motohide Shimazu
  • Marcus F Keep
  • Alexandr Jegorov
  • Eskil Elmer
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
Original languageEnglish
Pages (from-to)284-294
JournalFree Radical Biology & Medicine
Volume45
Publication statusPublished - 2008
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Brain Research (0131000120), Neurology, Lund (013027000), Clinical Neurophysiology (013013001), Department of Clinical Physiology (Lund) (013013000), Faculty of Medicine (000022000)

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