Interplay between intracellular Ca2+ oscillations and Ca2+-stimulated mitochondrial metabolism

Abstract

Oscillations of cytosolic Ca2+ concentration are a widespread mode of signalling. Oscillatory spikes rely on repetitive exchanges of Ca2+ between the endoplasmic reticulum (ER) and the cytosol, due to the regulation of inositol 1,4,5-trisphosphate receptors. Mitochondria also sequester and release Ca2+, thus affecting Ca2+ signalling. Mitochondrial Ca2+ activates key enzymes involved in ATP synthesis. We propose a new integrative model for Ca2+ signalling and mitochondrial metabolism in electrically non-excitable cells. The model accounts for (1) the phase relationship of the Ca2+ changes in the cytosol, the ER and mitochondria, (2) the dynamics of mitochondrial metabolites in response to cytosolic Ca2+ changes, and (3) the impacts of cytosol/mitochondria Ca2+ exchanges and of mitochondrial metabolism on Ca2+ oscillations. Simulations predict that as expected, oscillations are slowed down by decreasing the rate of Ca2+ efflux from mitochondria, but also by decreasing the rate of Ca2+ influx through the mitochondrial Ca2+ uniporter (MCU). These predictions were experimentally validated by inhibiting MCU expression. Despite the highly non-linear character of Ca2+ dynamics and mitochondrial metabolism, bioenergetics were found to be robust with respect to changes in frequency and amplitude of Ca2+ oscillations.