Impaired expression of the mitochondrial calcium uniporter suppresses mast cell degranulation.
Calcium ion (Ca(2+)) uptake into the mitochondrial matrix influences ATP production, Ca(2+) homeostasis, and apoptosis regulation. Ca(2+) uptake across the ion-impermeable inner mitochondrial membrane is mediated by the mitochondrial Ca(2+) uniporter (MCU) complex. The MCU complex forms a pore structure composed of several proteins. MCU is a Ca(2+)-selective channel in the inner-mitochondrial membrane that allows electrophoretic Ca(2+) entry into the matrix. Mitochondrial Ca(2+) uptake 1 (MICU1) functions as a Ca(2+)-sensing regulator of the MCU complex. Previously, by microscopic analysis at the single-cell level, we found that during mast cell activation, mitochondria capture cytosolic Ca(2+) in two steps. Consequently, mitochondrial Ca(2+) uptake likely plays a role in cellular function through cytosolic Ca(2+) buffering. Here, we investigate the role of MCU and MICU1 in mitochondrial Ca(2+) uptake and mast cell degranulation using MCU- and MICU1-knockdown (KD) mast cells. Whereas MCU- and MICU1-KD mast cells show normal proliferation rates and mitochondrial membrane potential, they exhibit slow and reduced cytosolic and mitochondrial Ca(2+) elevation after antigen stimulation. Moreover, β-hexosaminidase release induced by antigen was significantly suppressed in MCU-KD cells but not MICU1-KD cells. This suggests that both MCU and MICU1 are involved in mitochondrial Ca(2+) uptake in mast cells, while MCU plays a role in mast cell degranulation.
School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan. furuno@dpc.agu.ac.jp.
Tadahide
T
Furuno
School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
Narumi
N
Shinkai
School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
Yoshikazu
Y
Inoh
School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
Mamoru
M
Nakanishi
D000818:Animals; D000941:Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D015550:Cell Degranulation; D002460:Cell Line; D049109:Cell Proliferation; D004140:Dinitrophenols / Q000276:immunology; D005786:Gene Expression Regulation; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D012710:Serum Albumin, Bovine / Q000276:immunology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D000941:Antigens; D015220:Calcium Channels; D004140:Dinitrophenols; D033681:Mitochondrial Membrane Transport Proteins; C034638:dinitrophenyl-bovine serum albumin; C034703:mitochondrial calcium uniporter; D012710:Serum Albumin, Bovine; D002118:Calcium
Calcium; Degranulation; MCU; Mast cell; Mitochondria