Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport

Mitochondrial Ca2+ uptake is crucial for the regulation of the rate of oxidative phosphorylation(1), the modulation of spatiotemporal cytosolic Ca2+ signals(2,3,4) and apoptosis(5). Although the phenomenon of mitochondrial Ca2+ sequestration, its characteristics and physiological consequences have been convincingly reported(6,7), the actual protein(s) involved in this process are unknown. Here, we show that the uncoupling proteins 2 and 3 (UCP2 and UCP3) are essential for mitochondrial Ca2+ uptake. Using overexpression, knockdown (small interfering RNA) and mutagenesis experiments, we demonstrate that UCP2 and UCP3 are elementary for mitochondrial Ca2+ sequestration in response to cell stimulation under physiological conditions - observations supported by isolated liver mitochondria of Ucp2(-/)-mice lacking ruthenium red-sensitive Ca2+ uptake. Our results reveal a novel molecular function for UCP2 and UCP3, and may provide the molecular mechanism for their reported effects(8-10). Moreover, the identification of proteins fundemental for mitochondrial Ca2+ uptake expands our knowledge of the physiological role for mitochondrial Ca2+ sequestration.