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Cytoplasmic Na + ‐dependent modulation of mitochondrial Ca 2+ via electrogenic mitochondrial Na + –Ca 2+ exchange
Author(s) -
Kim Bongju,
Matsuoka Satoshi
Publication year - 2008
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.148726
Subject(s) - depolarization , membrane potential , chemistry , mitochondrion , cytoplasm , biophysics , inner mitochondrial membrane , ruthenium red , calcium , stereochemistry , biochemistry , biology , organic chemistry
To clarify the role of mitochondrial Na + –Ca 2+ exchange (NCX mito ) in regulating mitochondrial Ca 2+ (Ca 2+ mito ) concentration at intact and depolarized mitochondrial membrane potential (ΔΨ mito ), we measured Ca 2+ mito and ΔΨ mito using fluorescence probes Rhod‐2 and TMRE, respectively, in the permeabilized rat ventricular cells. Applying 300 n m cytoplasmic Ca 2+ (Ca 2+ c ) increased Ca 2+ mito and this increase was attenuated by cytoplasmic Na + (Na + c ) with an IC 50 of 2.4 m m . To the contrary, when ΔΨ mito was depolarized by FCCP, a mitochondrial uncoupler, Na + c enhanced the Ca 2+ c ‐induced increase in Ca 2+ mito with an EC 50 of about 4 m m . This increase was not significantly affected by ruthenium red or cyclosporin A. The inhibition of NCX mito by CGP‐37157 further increased Ca 2+ mito when ΔΨ mito was intact, while it suppressed the Ca 2+ mito increase when ΔΨ mito was depolarized, suggesting that ΔΨ mito depolarization changed the exchange mode from forward to reverse. Furthermore, ΔΨ mito depolarization significantly reduced the Ca 2+ mito decrease via forward mode, and augmented the Ca 2+ mito increase via reverse mode. When the respiratory chain was attenuated, the induction of the reverse mode of NCX mito hyperpolarized ΔΨ mito , while ΔΨ mito depolarized upon inducing the forward mode of NCX mito . Both changes in ΔΨ mito were remarkably inhibited by CGP‐37157. The above experimental data indicated that NCX mito is voltage dependent and electrogenic. This notion was supported theoretically by computer simulation studies with an NCX mito model constructed based on present and previous studies, presuming a consecutive and electrogenic Na + –Ca 2+ exchange and a depolarization‐induced increase in Na + flux. It is concluded that Ca 2+ mito concentration is dynamically modulated by Na + c and ΔΨ mito via electrogenic NCX mito .