17β-estradiol modulates mitochondrial Ca²⁺ flux in rat caudate nucleus and brain stem

The aim of this study was to examine the rapid non-genomic effect of 17β-estradiol (E2) on Ca²⁺ transport in mitochondria isolated from the nerve terminals (synaptosomes) of caudate nuclei (NC) and brain stems (BS) of ovariectomised female rats. In physiological conditions no effect of E2 on Ca²⁺ influx into synaptosomal mitochondria through ruthenium red (RR)-sensitive uniporter was observed. However, in the presence of uncoupling agent carbonyl cyanide4-(trifluoromethoxy)phenylhydrazone (FCCP) (1μmol/l), pre-treatment with 0.5nmol/l E2 protected mitochondrial membrane potential and consequently increased Ca²⁺ influx (2.3-fold in NC and 3.1-fold in BS). At the same time, 0.5nmol/l E2 by increasing the affinity of mitochondrial Na⁺/Ca²⁺ exchanger for Na⁺ inhibited mitochondrial Ca²⁺ efflux in NC and BS by about 40%. Also, the specific binding of physiological E2 concentrations (0.1-10nmol/l) to isolated synaptosomal mitochondria was detected. Using membrane impermeable E2 bound to bovine serum albumin and selective inhibitor of mitochondrial Na⁺/Ca²⁺ exchanger, we obtained that E2's action on mitochondrial Ca²⁺ efflux at least partially is due to the direct effects on the mitochondrial membrane and/or Na⁺/Ca²⁺ exchanger located in inner mitochondrial membrane. Our results implicate E2 as a modulator of Ca²⁺ concentration in mitochondrial matrix, and ultimately in the cytosol. Given the vital role of Ca²⁺ in regulation of total nerve cells activity, especially energy metabolism, neurotransmission and directing the cells toward survival or cell death, the effects on mitochondrial Ca²⁺ transport could be one of the important modes of E2 neuromodulatory action independent of the genome.