Calcium signal transmission between ryanodine receptors and mitochondria

Gábor Szalait, György Csordást, Basil M. Hantash, Andrew P. Thomas, György Hajnóczky

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

Abstract

Control of energy metabolism by increases of mitochondrial matrix [Ca2+] ([Ca2+](m)) may represent a fundamental mechanism to meet the ATP demand imposed by heart contractions, but the machinery underlying propagation of [Ca2+] signals from ryanodine receptor Ca2+ release channels (RyR) to the mitochondria remains elusive. Using permeabilized cardiac (H9c2) cells we investigated the cytosolic [Ca2+] ([Ca2+](c)) and [Ca2+](m) signals elicited by activation of RyR. Caffeine, Ca2+, and ryanodine evoked [Ca2+](c) spikes that often appeared as frequency- modulated [Ca2+](c) oscillations in these permeabilized cells. Rapid increases in [Ca2+](m) and activation of the Ca2+-sensitive mitochondrial dehydrogenases were synchronized to the rising phase of the [Ca2+](c) spikes. The RyR-mediated elevations of global [Ca2+](c) were in the submicromolar range, but the rate of [Ca2+](m) increases was as large as it was in the presence of 30 μM 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 result from large and rapid increases of perimitochondrial [Ca2+]. The falling phase of [Ca2+](c) spikes was followed by a rapid decay of [Ca2+](m). CGP37157 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 contribution from the permeability transition pore. Thus, rapid activation of Ca2+ uptake sites and Ca2+ exchangers evoked by RyR- mediated local [Ca2+](c) signals allow mitochondria to respond rapidly to single [Ca2+](c) spikes in cardiac cells.

Original languageEnglish (US)
Pages (from-to)15305-15313
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number20
DOIs
StatePublished - May 19 2000

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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