Lithium desensitizes brain mitochondria to calcium, antagonizes permeability transition, and diminishes cytochrome c release

Natalia Shalbuyeva, Tatiana Brustovetsky, Nikolai Broustovetski

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Abstract

Among the numerous effects of lithium on intracellular targets, its possible action on mitochondria remains poorly explored. In the experiments with suspension of isolated brain mitochondria, replacement of KCl by LiCl suppressed mitochondrial swelling, depolarization, and a release of cytochrome c induced by a single Ca2+ bolus. Li+ robustly protected individual brain mitochondria loaded with rhodamine 123 against Ca 2+-induced depolarization. In the experiments with slow calcium infusion, replacement of KCl by LiCl in the incubation medium increased resilience of synaptic and nonsynaptic brain mitochondria as well as resilience of liver and heart mitochondria to the deleterious effect of Ca2+. In LiCl medium, mitochondria accumulated larger amounts of Ca2+ before they lost the ability to sequester Ca2+. However, lithium appeared to be ineffective if mitochondria were challenged by Sr2+ instead of Ca2+. Cyclosporin A, sanglifehrin A, and Mg2+, inhibitors of the mitochondrial permeability transition (mPT), increased mitochondrial Ca2+ capacity in KCl medium but failed to do so in LiCl medium. This suggests that the mPT might be a common target for Li+ and mPT inhibitors. In addition, lithium protected mitochondria against high Ca 2+ in the presence of ATP, where cyclosporin A was reported to be ineffective. SB216763 and SB415286, inhibitors of glycogen synthase kinase-3β, which is implicated in regulating reactive oxygen species-induced mPT in cardiac mitochondria, did not increase Ca2+ capacity of brain mitochondria. Altogether, these findings suggest that Li + desensitizes mitochondria to elevated Ca2+ and diminishes cytochrome c release from brain mitochondria by antagonizing the Ca2+-induced mPT.

Original languageEnglish
Pages (from-to)18057-18068
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number25
DOIs
StatePublished - Jun 22 2007

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Mitochondria
Cytochromes c
Lithium
Permeability
Brain
Calcium
Depolarization
Cyclosporine
Mitochondrial Swelling
Rhodamine 123
Glycogen Synthase Kinase 3
Heart Mitochondria
Liver Mitochondrion
Liver
Reactive Oxygen Species
Suspensions
Swelling
Adenosine Triphosphate
Experiments

ASJC Scopus subject areas

  • Biochemistry

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Lithium desensitizes brain mitochondria to calcium, antagonizes permeability transition, and diminishes cytochrome c release. / Shalbuyeva, Natalia; Brustovetsky, Tatiana; Broustovetski, Nikolai.

In: Journal of Biological Chemistry, Vol. 282, No. 25, 22.06.2007, p. 18057-18068.

Research output: Contribution to journalArticle

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