RT info:eu-repo/semantics/article
T1 Calcineurin-independent inhibition of mitochondrial Ca2+ uptake by cyclosporin A
A1 Montero Zoccola, María Teresa
A1 Domínguez Lobatón, María Carmen
A1 Gutierrez-Fernández, S.
A1 Moreno Díaz-Calderón, Alfredo
A1 Álvarez Martín, Javier
K1 Calcio - Metabolismo
AB Cyclosporin A (CsA) is a widely used compound because ofits potent immunosupressiveproperties, derived mainly from the inhibition of calcineurin, and also because of its ability to blockthe mitochondrial permeability transition pore (PTP). This second effect has been involved in theprotection against apoptosis mediated by release ofmitochondrial factors. We show here that CsA (1–10mM) has an additional effect on Ca2+ homeostasis in mitochondria that cannot be attributed toinhibition ofPTP.By measuring specifically mitochondrial [Ca2+] with targeted aequorin, we show that CsAinhibited Ca2+ entry into mitochondria both in intact and in permeabilized cells, and this effect wasstronger when Ca2+ entry was triggered by low cytosolic [Ca2+], below 5 mM.Inhibition ofmitochondrial Ca2+ uptake required micromolar concentrations ofCsA and was notmimicked by other inhibitors of calcineurin such as FK-506 or cypermethrin, nor by a differentinhibitor ofthe PTP, bongkrekic acid.CsA blocked the increase in mitochondrial Ca2+ uptake rate induced by the mitochondrial Ca2+uniporter activator SB202190.5 Our results suggest that CsA inhibits Ca2+ entry through the Ca2+ uniporter by a mechanismindependent ofthe inhibition ofPTP or calcineurin. This effect may contribute to reducedepolarization and Ca2+ overloading in mitochondria after cell stimulation, and thus cooperatewith the direct inhibition ofPTP to prevent apoptosis.
PB Nature Publishing Group
SN 0007-1188
YR 2004
FD 2004
LK http://uvadoc.uva.es/handle/10324/5956
UL http://uvadoc.uva.es/handle/10324/5956
LA eng
NO British Journal of Pharmacology, 2004, vol. 141, n. 2, p. 263-268
NO Producción Científica
DS UVaDOC
RD 24-nov-2024