Published online before print December 19, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0705412

Received for publication July 26, 2005.
Revised October 30, 2005.
Accepted for publication October 31, 2005.

Article

Mitochondrial Ca²⁺ flux is a critical determinant of the Ca²⁺ dependence of mast cell degranulation

Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: ysuzuki{at}med.nihon-u.ac.jp.

Abstract

An increase in intracellular Ca²⁺ ([Ca²⁺]_i) is necessary for mast cell exocytosis, but there is controversy over the requirement for Ca²⁺ in the extracellular medium. Here, we demonstrate that mitochondrial function is a critical determinant of Ca²⁺ dependence. In the presence of extracellular Ca²⁺, mitochondrial metabolic inhibitors, including rotenone, antimycin A, and the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), significantly reduced degranulation induced by immunoglobulin E (IgE) antigen or by thapsigargin, as measured by -hexosaminidase release. In the absence of extracellular Ca²⁺; however, antimycin A and FCCP, but not rotenone, enhanced, rather than reduced, degranulation to a maximum of 76% of that observed in the presence of extracellular Ca²⁺. This enhancement of extracellular, Ca²⁺-independent degranulation was concomitant with a rapid collapse of the mitochondrial transmembrane potential. Mitochondrial depolarization did not enhance degranulation induced by thapsigargin, irrespective of the presence or absence of extracellular Ca²⁺. IgE antigen was more effective than thapsigargin as an inducer of [Ca²⁺]_i release, and mitochondrial depolarization augmented IgE-mediated but not thapsigargin-induced Ca²⁺ store release and mitochondrial Ca²⁺ ([Ca²⁺]_m) release. Finally, atractyloside and bongkrekic acid [an agonist and an antagonist, respectively, of the mitochondrial permeability transition pore (mPTP)], respectively, augmented and reduced IgE-mediated Ca²⁺ store release, [Ca²⁺]_m release, and/or degranulation, whereas they had no effects on thapsigargin-induced Ca²⁺ store release. These data suggest that the mPTP is involved in the regulation of Ca²⁺ signaling, thereby affecting the mode of mast cell degranulation. This finding may shed light on a new role for mitochondria in the regulation of mast cell activation.

Key Words: signal transduction • Ca²⁺ • mitochondria • permeability transition pore

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