HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 49, 37547-37558, December 8, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/49/37547    most recent M607263200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shalbuyeva, N. Articles by Brustovetsky, N. Search for Related Content PubMed PubMed Citation Articles by Shalbuyeva, N. Articles by Brustovetsky, N. Social Bookmarking                      What's this?

Calcium-dependent Spontaneously Reversible Remodeling of Brain Mitochondria^*

Natalia Shalbuyeva, Tatiana Brustovetsky, Alexey Bolshakov¹, and Nickolay Brustovetsky²

From the Department of Pharmacology and Toxicology, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202

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 Sr²⁺ 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, and Mg²⁺, 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.

Received for publication, July 31, 2006 , and in revised form, October 10, 2006.

^* This work was supported by NINDS Grant R01 NS 050131 from the National Institutes of Health (to N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–10.

¹ Present address: Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiiskaya Str. 8, 125315 Moscow, Russia.

² To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., Medical Science Bldg., Rm. 549, Indianapolis, IN 46202. Tel.: 317-278-9229; Fax: 317-274-7714; E-mail: nbrous{at}iupui.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Shalbuyeva, T. Brustovetsky, and N. Brustovetsky Lithium Desensitizes Brain Mitochondria to Calcium, Antagonizes Permeability Transition, and Diminishes Cytochrome c Release J. Biol. Chem., June 22, 2007; 282(25): 18057 - 18068. [Abstract] [Full Text] [PDF]