title: Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism.
abstract: Oscillations of cytosolic Ca(2+) concentration are a widespread mode of signalling. Oscillatory spikes rely on repetitive exchanges of Ca(2+) between the endoplasmic reticulum (ER) and the cytosol, due to the regulation of inositol 1,4,5-trisphosphate receptors. Mitochondria also sequester and release Ca(2+), thus affecting Ca(2+) signalling. Mitochondrial Ca(2+) activates key enzymes involved in ATP synthesis. We propose a new integrative model for Ca(2+) signalling and mitochondrial metabolism in electrically non-excitable cells. The model accounts for (1) the phase relationship of the Ca(2+) changes in the cytosol, the ER and mitochondria, (2) the dynamics of mitochondrial metabolites in response to cytosolic Ca(2+) changes, and (3) the impacts of cytosol/mitochondria Ca(2+) exchanges and of mitochondrial metabolism on Ca(2+) oscillations. Simulations predict that as expected, oscillations are slowed down by decreasing the rate of Ca(2+) efflux from mitochondria, but also by decreasing the rate of Ca(2+) influx through the mitochondrial Ca(2+) uniporter (MCU). These predictions were experimentally validated by inhibiting MCU expression. Despite the highly non-linear character of Ca(2+) dynamics and mitochondrial metabolism, bioenergetics were found to be robust with respect to changes in frequency and amplitude of Ca(2+) oscillations.
authors.affiliation: Unité de Chronobiologie Théorique, Université Libre de Bruxelles, CP231, Boulevard du Triomphe, 1050, Brussels, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wacquier
authors.affiliation: Université Paris Sud, UMRS1174, Orsay F-91405, France.|Institut National de la Santé et de la Recherche Médicale (Inserm), UMRS1174, Orsay F-91405, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Combettes
authors.affiliation: Equipe Communication Intercellulaire et Infections Microbiennes, Centre de Recherche Interdisciplinaire en Biologie(CIRB), Collège de France, 11 Place Marcelin Berthelot, Paris 75005, France.|Inserm, U1050, Paris 75005, France.|Centre national de la Recherche Scientifique (CNRS), UMR7241, Paris 75005, France.|MEMOLIFE Laboratory of excellence and Paris Sciences et Lettres, Paris 75005, France.
authors.forename: Guy Tran
authors.initials: GT
authors.lastname: Van Nhieu
authors.affiliation: Unité de Chronobiologie Théorique, Université Libre de Bruxelles, CP231, Boulevard du Triomphe, 1050, Brussels, Belgium.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dupont
mesh_terms: D000465:Algorithms; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D002118:Calcium