Calcium signal transmission between ryanodine receptors and mitochondria

Control of energy metabolism by increases of mitochondrial matrix [Ca2+] ([ Ca2+](m)) may represent a fundamental mechanism to meet the ATP demand impo sed by heart contractions, but the machinery underlying propagation of [Ca2 +] signals from ryanodine receptor Ca2+ release channels (RyR) to the mitoc hondria remains elusive. Using permeabilized cardiac (H9c2) cells we invest igated the cytosolic [Ca2+] ([Ca2+](c)) and [Ca2+](m) signals elicited by a ctivation of RyR, Caffeine, Ca2+, and ryanodine evoked [Ca2+](c) spikes tha t often appeared as frequency-modulated [Ca2+](c) oscillations in these per meabilized cells. Rapid increases in [Ca2+], and activation of the Ca2+-sen sitive mitochondrial dehydrogenases were synchronized to the rising phase o f the [Ca2+](c) spikes, The RyR-mediated elevations of global [Ca2+](c) wer e in the submicromolar range, but the rate of [Ca2+](m) increases was as la rge as it was in the presence of 30 mu M global [Ca2+](c). Furthermore, RyR -dependent increases of [Ca2+](m) were relatively insensitive to buffering of [Ca2+](c) by EGTA. Therefore, RyR-driven rises of [Ca2+](m) appear to re sult from large and rapid increases of perimitochondrial [Ca2+]. The fallin g phase of [Ca2+](c) spikes was followed by a rapid decay of [Ca2+](m). CGP 37157 slowed down relaxation of [Ca2+](m) spikes, whereas cyclosporin A had no effect, suggesting that activation of the mitochondrial Ca2+ exchangers accounts for rapid reversal of the [Ca2+](m) response with little contribu tion from the permeability transition pore. Thus, rapid activation of Ca2uptake sites and Ca2+ exchangers evoked by RyR-mediated local [Ca2+](c) sig nals allow mitochondria to respond rapidly to single [Ca2+](c) spikes in ca rdiac cells.