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

Abstract: 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. [Copyright &y& Elsevier]