Modulation of mitochondrial Ca 2+ uptake by estrogen receptor agonists and antagonists

1 Ca 2+ uptake by mitochondria is a key element in the control of cellular Ca 2+ homeostasis and Ca 2+ ‐dependent phenomena. It has been known for many years that this Ca 2+ uptake is mediated by the mitochondrial Ca 2+ uniporter, a specific Ca 2+ channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter. 2 The specific α ‐ER agonist 4,4′,4″‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca 2+ uptake in permeabilized HeLa cells by 10‐fold at 2  μ M . Consistently, PPT largely increased the histamine‐induced mitochondrial [Ca 2+ ] peak and reduced the cytosolic one. 3 Diethylstilbestrol and 17‐ β ‐estradiol (but not 17‐ α ‐estradiol) were active at pharmacological concentrations while the β ‐estrogen‐receptor agonist 2,3‐bis(4‐hydroxyphenyl)‐propionitrile (DPN) was little effective. 4 The ER modulators tamoxifen and 4‐hydroxy‐tamoxifen inhibited mitochondrial Ca 2+ uptake (IC 50 2.5±1.5 and 2.5±1.4  μ M , mean±s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect. 5 Activation by PPT was immediate and inhibition by tamoxifen or 4‐hydroxy‐tamoxifen required only 5 min to reach maximum. 6 Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca 2+ uptake. 7 These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca 2+ uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported effects of these compounds.British Journal of Pharmacology (2005) 145 , 862–871. doi: 10.1038/sj.bjp.0706265