title: 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.
abstract: Novel findings that emerged from this study underscore the fact that the dynamic nature of mitochondria leads to functional heterogeneity of [Ca(2+)](mito) with respect to estrogen actions in MCF7 cells. We show that estrogen exposure to cells increased [Ca(2+)](mito) in a high-calcium capacity mitochondrial population but not in low-calcium capacity mitochondria. Physiological concentrations of 17beta-estradiol (E2) modulated Ca(2+)(mito) uptake within 90 s. Interestingly, this calcium response lagged behind the induction of mitochondrial reactive oxygen species (mtROS). The rapid induction of Ca(2+)(mito) 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(2+)(mito) and/or mtROS promotes oxidative signaling without involving nuclear estrogen receptor signaling. Although the early E2-induced Ca(2+) did not alter the expression of genes involved in calcium signaling pathways, an intracellular calcium chelator BAPTA-AM and the Ca(2+)(mito) 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(2+)(mito) are involved in cell cycle progression presumably through the control of early cell cycle genes. Targeting mitochondria to disrupt communication between mitochondria and ROS/Ca(2+) signaling pathways may provide the basis for a novel anticancer strategy for the treatment of estrogen-dependent breast cancer.
authors.affiliation: Department of Environmental and Occupational Health, Robert Stempel School of Public Health, Florida International University, Miami, Florida 33199, USA.
authors.forename: Jai
authors.initials: J
authors.lastname: Parkash
authors.forename: Quentin
authors.initials: Q
authors.lastname: Felty
authors.forename: Deodutta
authors.initials: D
authors.lastname: Roy
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; D017382:Reactive Oxygen Species; D002118:Calcium