title: Mitochondrial Ca2+ flux is a critical determinant of the Ca2+ dependence of mast cell degranulation.
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.affiliation: 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.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001278:Atractyloside / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D015550:Cell Degranulation / Q000276:immunology / Q000502:physiology*; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D012402:Rotenone; D001865:Bongkrekic Acid; D001278:Atractyloside; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D007073:Immunoglobulin E; D000968:Antimycin A; D019284:Thapsigargin; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium