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Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation.
J Leukoc Biol. 2006 Mar; 79(3):508-18.JL

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 beta-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.

Authors+Show Affiliations

Divisionof Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchikami-cho Itabashi-ku, Tokyo 173-8610, Japan. ysuzuki@med.nihon-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16365155

Citation

Suzuki, Yoshihiro, et al. "Mitochondrial Ca2+ Flux Is a Critical Determinant of the Ca2+ Dependence of Mast Cell Degranulation." Journal of Leukocyte Biology, vol. 79, no. 3, 2006, pp. 508-18.
Suzuki Y, Yoshimaru T, Inoue T, et al. Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation. J Leukoc Biol. 2006;79(3):508-18.
Suzuki, Y., Yoshimaru, T., Inoue, T., & Ra, C. (2006). Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation. Journal of Leukocyte Biology, 79(3), 508-18.
Suzuki Y, et al. Mitochondrial Ca2+ Flux Is a Critical Determinant of the Ca2+ Dependence of Mast Cell Degranulation. J Leukoc Biol. 2006;79(3):508-18. PubMed PMID: 16365155.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation. AU - Suzuki,Yoshihiro, AU - Yoshimaru,Tetsuro, AU - Inoue,Toshio, AU - Ra,Chisei, Y1 - 2005/12/19/ PY - 2005/12/21/pubmed PY - 2006/5/4/medline PY - 2005/12/21/entrez SP - 508 EP - 18 JF - Journal of leukocyte biology JO - J Leukoc Biol VL - 79 IS - 3 N2 - 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 beta-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. SN - 0741-5400 UR - https://www.unboundmedicine.com/medline/citation/16365155/Mitochondrial_Ca2+_flux_is_a_critical_determinant_of_the_Ca2+_dependence_of_mast_cell_degranulation_ L2 - https://doi.org/10.1189/jlb.0705412 DB - PRIME DP - Unbound Medicine ER -