Distinct properties of Ca efflux from brain, heart and liver mitochondria: The effects of Na, Li and the mitochondrial Na/Ca exchange inhibitor CGP37157.

Mitochondrial Ca transport is essential for regulating cell bioenergetics, Ca signaling and cell death. Mitochondria accumulate Ca via the mitochondrial Ca uniporter (MCU), whereas Ca is extruded by the mitochondrial Na/Ca (mtNCX) and H/Ca exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca overload. Recent work demonstrated that MCU activity varies significantly among tissues, likely reflecting tissue-specific Ca signaling and energy needs. It is less clear whether this diversity in MCU activity is matched by tissue-specific diversity in mitochondrial Ca extrusion. Here we compared properties of mitochondrial Ca extrusion in three tissues with prominent mitochondria function: brain, heart and liver. At the transcript level, expression of the Na/Ca/Li exchanger (NCLX), which has been proposed to mediate mtNCX transport, was significantly greater in liver than in brain or heart. At the functional level, Na robustly activated Ca efflux from brain and heart mitochondria, but not from liver mitochondria. The mtNCX inhibitor CGP37157 blocked Ca efflux from brain and heart mitochondria but had no effect in liver mitochondria. Replacement of Na with Li to test the involvement of NCLX, resulted in a slowing of mitochondrial Ca efflux by ∼70 %. Collectively, our findings suggest that mtNCX is responsible for Ca extrusion from the mitochondria of the brain and heart, but plays only a small, if any, role in mitochondria of the liver. They also reveal that Li is significantly less effective than Na in driving mitochondrial Ca efflux.