A model of mitochondrial Ca 2+-induced Ca 2+ release simulating the Ca 2+ oscillations and spikes generated by mitochondria

Abstract

Recent evidence underlines a key role of mitochondrial Ca 2+ fluxes in cell Ca 2+ signalling. We present here a kinetic model simulating the Ca 2+ fluxes generated by mitochondria during mitochondrial Ca 2+-induced Ca 2+ release (mCICR) resulting from the operation of the permeability transition pore (PTP). Our model connects the Ca 2+ fluxes through the ruthenium red-sensitive Ca 2+ uniporter, the respiration-dependent and passive H + fluxes, the rate of oxygen consumption, the movements of weak acids across the mitochondrial membrane, the electrical transmembrane potential ( Δ Ψ), 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 closure on matrix pH (pH i), and (ii) the relative inhibition of the respiratory rate consecutive to PTP opening. The resulting model can simulate irreversible Ca 2+ efflux from mitochondria, as well as the genesis of damped or sustained Ca 2+ oscillations, and of single Ca 2+ spikes. The model also simulates the main features of mCICR, i.e. the threshold-dependence of mCICR triggering, and the all-or-nothing nature of mCICR operation. Our model should appear useful to further mathematically address the consequences of mCICR on the spatiotemporal organisation of Ca 2+ signals, as a `plug-in' module for the existing models of cell Ca 2+ signalling.