Distinct properties of Ca2+ efflux from brain, heart and liver mitochondria: The effects of Na+, Li+ and the mitochondrial Na+/Ca2+ exchange inhibitor CGP37157

Abstract

Mitochondrial Ca²⁺ transport is essential for regulating cell bioenergetics, Ca²⁺ signaling and cell death. Mitochondria accumulate Ca²⁺ via the mitochondrial Ca²⁺ uniporter (MCU), whereas Ca²⁺ is extruded by the mitochondrial Na⁺/Ca²⁺ (mtNCX) and H⁺/Ca²⁺ exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca²⁺ overload. Recent work demonstrated that MCU activity varies significantly among tissues, likely reflecting tissue-specific Ca²⁺ signaling and energy needs. It is less clear whether this diversity in MCU activity is matched by tissue-specific diversity in mitochondrial Ca²⁺ extrusion. Here we compared properties of mitochondrial Ca²⁺ extrusion in three tissues with prominent mitochondria function: brain, heart and liver. At the transcript level, expression of the Na⁺/Ca²⁺/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 Ca²⁺ efflux from brain and heart mitochondria, but not from liver mitochondria. The mtNCX inhibitor CGP37157 blocked Ca²⁺ 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 Ca²⁺ efflux by ∼70 %. Collectively, our findings suggest that mtNCX is responsible for Ca²⁺ 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 Ca²⁺ efflux.

Keywords: Ca(2+) transport; Hippocampal neurons; Mitochondria; NCLX; NCX.