title: Ca2+-mediated mitochondrial reactive oxygen species metabolism augments Wnt/β-catenin pathway activation to facilitate cell differentiation.
abstract: Emerging evidence suggests that reactive oxygen species (ROS) can stimulate the Wnt/β-catenin pathway in a number of cellular processes. However, potential sources of endogenous ROS have not been thoroughly explored. Here, we show that growth factor depletion in human neural progenitor cells induces ROS production in mitochondria. Elevated ROS levels augment activation of Wnt/β-catenin signaling that regulates neural differentiation. We find that growth factor depletion stimulates the release of Ca(2+) from the endoplasmic reticulum stores. Ca(2+) subsequently accumulates in the mitochondria and triggers ROS production. The inhibition of mitochondrial Ca(2+) uptake with simultaneous growth factor depletion prevents the rise in ROS metabolism. Moreover, low ROS levels block the dissociation of the Wnt effector Dishevelled from nucleoredoxin. Attenuation of the response amplitudes of pathway effectors delays the onset of the Wnt/β-catenin pathway activation and results in markedly impaired neuronal differentiation. Our findings reveal Ca(2+)-mediated ROS metabolic cues that fine-tune the efficiency of cell differentiation by modulating the extent of the Wnt/β-catenin signaling output.
authors.affiliation: From Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125 Berlin-Buch and Cell Biology and Biosystems Technology, Institute of Biological Sciences, and Live Cell Imaging Center, University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany.
authors.forename: Tareck
authors.initials: T
authors.lastname: Rharass
authors.affiliation: Cell Biology and Biosystems Technology, Institute of Biological Sciences, and Live Cell Imaging Center, University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Lemcke
authors.affiliation: Cell Biology and Biosystems Technology, Institute of Biological Sciences, and.
authors.forename: Margareta
authors.initials: M
authors.lastname: Lantow
authors.affiliation: Live Cell Imaging Center, University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
authors.affiliation: Cell Biology and Biosystems Technology, Institute of Biological Sciences, and Live Cell Imaging Center, University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany.
authors.forename: Dieter G
authors.initials: DG
authors.lastname: Weiss
authors.affiliation: From Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125 Berlin-Buch and daniela.panakova@mdc-berlin.de.
authors.forename: Daniela
authors.initials: D
authors.lastname: Panáková
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D051176:beta Catenin; D002118:Calcium
keywords: Calcium Signaling; Dishevelled; Human Neural Progenitor Cells; Mitochondrial Metabolism; Nucleoredoxin; Reactive Oxygen Species (ROS); Redox Signaling; Wnt Pathway