Mitochondrial Calcium Uniporter MCU Supports Cytoplasmic Ca(2+) Oscillations, Store-Operated Ca(2+) Entry and Ca(2+)-Dependent Gene Expression in Response to Receptor Stimulation

Ca(2+) flux into mitochondria is an important regulator of cytoplasmic Ca(2+) signals, energy production and cell death pathways. Ca(2+) uptake can occur through the recently discovered mitochondrial uniporter channel (MCU) but whether the MCU is involved in shaping Ca(2+) signals and downstream responses to physiological levels of receptor stimulation is unknown. Here, we show that modest stimulation of leukotriene receptors with the pro-inflammatory signal LTC(4) evokes a series of cytoplasmic Ca(2+) oscillations that are rapidly and faithfully propagated into mitochondrial matrix. Knockdown of MCU or mitochondrial depolarisation, to reduce the driving force for Ca(2+) entry into the matrix, prevents the mitochondrial Ca(2+) rise and accelerates run down of the oscillations. The loss of cytoplasmic Ca(2+) oscillations appeared to be a consequence of enhanced Ca(2+)-dependent inactivation of InsP(3) receptors, which arose from the loss of mitochondrial Ca(2+) buffering. Ca(2+) dependent gene expression in response to leukotriene receptor activation was suppressed following knockdown of the MCU. In addition to buffering Ca(2+) release, mitochondria also sequestrated Ca(2+) entry through store-operated Ca(2+) channels and this too was prevented following loss of MCU. MCU is therefore an important regulator of physiological pulses of cytoplasmic Ca(2+).