Estrogen exerts a spatial and temporal influence on reactive oxygen species generation that precedes calcium uptake in high-capacity mitochondria: Implications for rapid nongenomic signaling of cell growth

Novel findings that emerged from this study underscore the fact that the dynamic nature of mitochondria leads to functional heterogeneity of [Ca2+](mito) with respect to estrogen actions in MCF7 cells. We show that estrogen exposure to cells increased [Ca2+](mito) in a high-calcium capacity mitochondrial population but not in low-calcium capacity mitochondria. Physiological concentrations of 17 beta-estradiol (E2) modulated Ca-mito(2+) to uptake within 90 s. Interestingly, this calcium response lagged behind the induction of mitochondrial reactive oxygen species (mtROS). The rapid induction of Ca-mito(2+) in response to E2 and its inhibition by mitochondrial blockers suggest that mitochondria are early nongenomic targets of E2. This suggests that a subpopulation of mitochondria is recruited to respond to new metabolic requirements required by estrogen triggers or, as in this case, E2-induced Ca-mito(2+) and/or mtROS promotes oxidative signaling without involving nuclear estrogen receptor signaling. Although the early E2-induced Ca2+ did not alter the expression of genes involved in calcium signaling pathways, an intracellular calcium chelator BAPTA-AM and the Ca-mito(2+) to uniporter blocker ruthenium red prevented E2-induced cell growth. We have shown recently that E2-mediated ROS production controls the promoter activity of cyclin D1 by post-translational modification of calcium sensitive transcription factor CREB. The findings of this study offer a new paradigm that rapid E2-induced changes in mtROS and Ca-mito(2+) are involved in cell cycle progression presumably through the control of early cell cycle genes. Targeting mitochondria to disrupt communication between mitochondria and ROS/Ca2+ signaling pathways may provide the basis for a novel anticancer strategy for the treatment of estrogen-dependent breast cancer.