Interplay Between Intracellular Ca2+ Oscillations and Ca2+-stimulated Mitochondrial Metabolism

Oscillations of cytosolic Ca 2+ concentration are a widespread mode of signalling. Oscillatory spikes rely on repetitive exchanges of Ca 2+ between the endoplasmic reticulum (ER) and the cytosol, due to the regulation of inositol 1,4,5-trisphosphate receptors. Mitochondria also sequester and release Ca 2+ , thus affecting Ca 2+ signalling. Mitochondrial Ca 2+ activates key enzymes involved in ATP synthesis. We propose a new integrative model for Ca 2+ signalling and mitochondrial metabolism in electrically non-excitable cells. The model accounts for (1) the phase relationship of the Ca 2+ changes in the cytosol, the ER and mitochondria, (2) the dynamics of mitochondrial metabolites in response to cytosolic Ca 2+ changes, and (3) the impacts of cytosol/mitochondria Ca 2+ exchanges and of mitochondrial metabolism on Ca 2+ oscillations. Simulations predict that as expected, oscillations are slowed down by decreasing the rate of Ca 2+ efflux from mitochondria, but also by decreasing the rate of Ca 2+ influx through the mitochondrial Ca 2+ uniporter (MCU). These predictions were experimentally validated by inhibiting MCU expression. Despite the highly non-linear character of Ca 2+ dynamics and mitochondrial metabolism, bioenergetics were found to be robust with respect to changes in frequency and amplitude of Ca 2+ oscillations.