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J Biol Chem, Vol. 273, Issue 17, 10223-10231, April 24, 1998
From the Ruthenium red is a well known inhibitor of
Ca2+ uptake into mitochondria in vitro.
However, its utility as an inhibitor of Ca2+ uptake into
mitochondria in vivo or in situ in intact cells
is limited because of its inhibitory effects on sarcoplasmic reticulum Ca2+ release channel and other cellular processes. We have
synthesized a ruthenium derivative and found it to be an oxygen-bridged
dinuclear ruthenium amine complex. It has the same chemical structure
as Ru360 reported previously (Emerson, J., Clarke, M. J., Ying,
W-L., and Sanadi, D. R. (1993) J. Am. Chem. Soc.
115, 11799-11805). Ru360 has been shown to be a potent inhibitor of
Ca2+-stimulated respiration of liver mitochondria in
vitro. However, the specificity of Ru360 on Ca2+
uptake into mitochondria in vitro or in intact cells has
not been determined. The present study reports in detail the potency, the effectiveness, and the mechanism of inhibition of mitochondrial Ca2+ uptake by Ru360 and its specificity in
vitro in isolated mitochondria and in situ in
isolated cardiac myocytes. Ru360 was more potent (IC50 = 0.184 nM) than ruthenium red (IC50 = 6.85 nM) in inhibiting Ca2+ uptake into
mitochondria. 103Ru360 was found to bind to isolated
mitochondria with high affinity (Kd = 0.34 nM, Bmax = 80 fmol/mg of
mitochondrial protein). The IC50 of 103Ru360
for the inhibition of Ca2+ uptake into mitochondria was
also 0.2 nM, indicating that saturation of a specific
binding site is responsible for the inhibition of Ca2+
uptake. Ru360, as high as 10 µM, produced no effect on
sarcoplasmic reticulum Ca2+ uptake or release, sarcolemmal
Na+/Ca2+ exchange, actomyosin ATPase activity,
L-type Ca2+ channel current, cytosolic Ca2+
transients, or cell shortening. 103Ru360 was taken up by
isolated myocytes in a time-dependent biphasic manner.
Ru360 (10 µM) applied outside intact voltage-clamped
ventricular myocytes prevented Ca2+ uptake into
mitochondria in situ where the cells were progressively loaded with Ca2+ via sarcolemmal
Na+/Ca2+ exchange by depolarization to +110 mV.
We conclude that Ru360 specifically blocks Ca2+ uptake into
mitochondria and can be used in intact cells.
Oxygen-bridged Dinuclear Ruthenium Amine Complex Specifically
Inhibits Ca2+ Uptake into Mitochondria in Vitro
and in Situ in Single Cardiac Myocytes
,,,,
,,, and Departments of Pharmacology
and Cell Biophysics, Chemistry, and
Molecular and Cellular Physiology,
University of Cincinnati, Cincinnati, Ohio 45267-0575, ¶ Department of Physiology, Loyola University, Maywood,
Illinois 60153, and ** Department of Medical Biochemistry, Ohio State
University, Columbus, Ohio 43210
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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