The contribution of UCP2 and UCP3 to mitochondrial Ca2+ uptake is differentially determined by the source of supplied Ca2+

The transmission of Ca2+ signals to mitochondria is an important phenomenon in cell signaling. We have recently reported that the novel uncoupling proteins UCP2 and UCP3 (UCP2/3) are fundamental for mitochondrial Ca2+ uniport (MCU). In the present study we investigate the contribution of UCP2/3 to mitochondrial accumulation of Ca2+ either exclusively released from the ER or entering the cell via the store-operated Ca2+ entry (SOCE) pathway. Using siRNA we demonstrate that constitutively expressed UCP2/3 are essentially involved in mitochondrial sequestration of intracellularly released Ca2+ but not of that entering the cells via SOCE. However, overexpression of UCP2/3 yielded elevated mitochondrial Ca2+ uptake from both sources, though it was more pronounced in case of entering Ca2+, indicating that the expression levels of UCP2/3 are crucial for the capacity of mitochondria to sequester entering Ca2+. Our data point to distinct UCP2/3-dependent and UCP2/3-independent modes of mitochondrial Ca2+ sequestration, which may meet the various demands necessary for an adequate organelle Ca2+ loading from different Ca2+ sources in intact cells.