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

Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts

“…The characteristics of the NCX mit current in forward mode, i.e., an extra-mitochondrial Na + -induced inward current with Ca 2+ in the pipette, corresponded well to those in previous reports-the currents were diminished by the NCX mit inhibitor CGP-37157 [32,33], the Hill coefficient for cytosolic Na + was around 3-4 [29,32], and Li + can be substitutable for Na + with ~70% lower efficacy [23,24]. One deviation was that the half-maximum concentration for Na + , 35.6 mM, was higher than the reported value of 1-8 mM in the heart (8 mM in [29]; 1 mM in [32]), possibly because the Na + -permeable background current could exist in the mitoplast preparations.…”

“…One deviation was that the half-maximum concentration for Na + , 35.6 mM, was higher than the reported value of 1-8 mM in the heart (8 mM in [29]; 1 mM in [32]), possibly because the Na + -permeable background current could exist in the mitoplast preparations. The lower efficacy of Li + compared to Na + in exchanging for Ca 2+ was also reported in brain mitochondria, to a similar extent as in the heart [10,23]. Through molecular modeling analysis based on Metanococcus jannaschii NCX_Mj and Archaeoglobus fulgidus CAX_Af, combined with functional analysis of human NCLX mutants, distinct amino acid residues in NCLX were identified as determining Na + or Li + binding [34].…”

“…Interestingly, they found that the expression level of the Letm1 protein in mitochondria was higher in the heart than in the liver, though the functional contribution of HCX mit was much higher in the liver than in the heart. Post-translational modifications or extra-mitochondrial localization of Letm1 protein in the heart, just as reported for NCLX [23], may explain the disparity between the expression level and function.…”

“…In order to balance against the mitochondrial Ca 2+ influx, NCX mit and H + -Ca 2+ exchange (HCX mit ) extrude Ca 2+ from mitochondria, with the former accounting for the major component in excitable tissues such as the heart and brain, and the latter being dominant in non-excitable tissues such as the liver and kidney (see review [22]). Rysted et al [23] quantitatively compared the NCX mit activity in mitochondria isolated from mouse brains, livers, and hearts. By evaluating extra-mitochondrial Ca 2+ using Calcium Green-5N, they demonstrated that the rate of Na + -dependent Ca 2+ efflux from mitochondria was ~3-fold larger in the brain than in the heart.…”

“…In the heart, the fraction of Na + -dependent Ca 2+ efflux to total Ca 2+ efflux is 60-100%, depending on species and experimental conditions [8,[23][24][25]. The remaining fraction should be mediated by HCX mit , though its contribution in the heart has been controversial.…”