Calcium-dependent spontaneously reversible remodeling of brain mitochondria

Natalia Shalbuyeva, Tatiana Brustovetsky, Alexey Bolshakov, Nikolai Broustovetski

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

An exposure of cultured hippocampal neurons expressing mitochondrially targeted enhanced yellow fluorescent protein to excitotoxic glutamate resulted in reversible mitochondrial remodeling that in many instances could be interpreted as swelling. Remodeling was not evident if glutamate receptors were blocked with MK801, if Ca2+ was omitted or substituted for Sr 2+ in the bath solution, if neurons were treated with carbonylcyanide p-trifluoromethoxyphenylhydrazone to depolarize mitochondria, or if neurons were pretreated with cyclosporin A or N-methyl-4-isoleucine-cyclosporin (NIM811) to inhibit the mitochondrial permeability transition. In the experiments with isolated brain synaptic or nonsynaptic mitochondria, Ca2+ triggered transient, spontaneously reversible cyclosporin A-sensitive swelling closely resembling remodeling of organelles in cultured neurons. The swelling was accompanied by the release of cytochrome c, Smac/DIABLO, Omi/HtrA2, and AIF but not endonuclease G. Depolarization with carbonylcyanide p- trifluoromethoxyphenylhydrazone or inhibition of the Ca2+ uniporter with Ru360 prevented rapid onset of the swelling. Sr2+ depolarized mitochondria but failed to induce swelling. Neither inhibitors of the large conductance Ca2+-activated K+ channel (charybdotoxin, iberiotoxin, quinine, and Ba2+) nor inhibitors of the mitochondrial ATP-sensitive K+ channel (5-hydroxydecanoate and glibenclamide) suppressed swelling. Quinine, dicyclohexylcarbodiimide, andMg2+, inhibitors of the mitochondrial K+/H+ exchanger, as well as external alkalization inhibited a recovery phase of the reversible swelling. In contrast to brain mitochondria, liver and heart mitochondria challenged with Ca2+ experienced sustained swelling without spontaneous recovery. The proposed model suggests an involvement of the Ca2+-dependent transient K+ influx into the matrix causing mitochondrial swelling followed by activation of the K+/H+ exchanger leading to spontaneous mitochondrial contraction both in situ and in vitro.

Original languageEnglish
Pages (from-to)37547-37558
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number49
DOIs
StatePublished - Dec 8 2006

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Mitochondria
Swelling
Brain
Potassium-Hydrogen Antiporters
Calcium
Cyclosporine
Neurons
Quinine
Mitochondrial Swelling
Charybdotoxin
Dicyclohexylcarbodiimide
Calcium-Activated Potassium Channels
Heart Mitochondria
Isoleucine
Glyburide
Liver Mitochondrion
Glutamate Receptors
Cytochromes c
Baths
Organelles

ASJC Scopus subject areas

  • Biochemistry

Cite this

Calcium-dependent spontaneously reversible remodeling of brain mitochondria. / Shalbuyeva, Natalia; Brustovetsky, Tatiana; Bolshakov, Alexey; Broustovetski, Nikolai.

In: Journal of Biological Chemistry, Vol. 281, No. 49, 08.12.2006, p. 37547-37558.

Research output: Contribution to journalArticle

Shalbuyeva, Natalia ; Brustovetsky, Tatiana ; Bolshakov, Alexey ; Broustovetski, Nikolai. / Calcium-dependent spontaneously reversible remodeling of brain mitochondria. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 49. pp. 37547-37558.
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