A MODEL OF MITOCHONDRIAL CA2-INDUCED CA2+ RELEASE SIMULATING THE CA2+OSCILLATIONS AND SPIKES GENERATED BY MITOCHONDRIA()

Recent evidence underlines a key role of mitochondrial Ca2+ fluxes in cell Ca2+ signalling. We present here a kinetic model simulating the C a2+ fluxes generated by mitochondria during mitochondrial Ca2+-induced Ca2+ release (mCICR) resulting from the operation of the permeability transition pore (PTP). Our model connects the Ca2+ fluxes through the ruthenium red-sensitive Ca2+ uniporter, the respiration-dependent and passive HC fluxes, the rate of oxygen consumption, the movements of w eak acids across the mitochondrial membrane, the electrical transmembr ane potential (Delta Psi), and operation of the PTP. We find that two factors are crucial to account for the various mCICR profiles that can be observed experimentally: (i) the dependence of PTP opening and clo sure on matrix pH (pH(i)), and (ii) the relative inhibition of the res piratory rate consecutive to PTP opening. The resulting model can simu late irreversible Ca2+ efflux from mitochondria, as well as the genesi s of damped or sustained Ca2+ oscillations, and of single Ca2+ spikes. The model also simulates the main features of mCICR, i.e. the thresho ld-dependence of mCICR triggering, and the all-or-nothing nature of mC ICR operation. Our model should appear useful to further mathematicall y address the consequences of mCICR on the spatiotemporal organisation of Ca2+ signals, as a 'plug-in' module for the existing models of cel l Ca2+ signalling. (C) 1998 Elsevier Science B.V. All rights reserved.