Ca2+-mediated Mitochondrial Reactive Oxygen Species Metabolism Augments Wnt/β-Catenin Pathway Activation to Facilitate Cell Differentiation*
| Autor: | Tareck Rharass, Heiko Lemcke, Daniela Panáková, Margareta Lantow, Dieter G. Weiss, Sergei A. Kuznetsov |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Beta-catenin
Nucleoredoxin Cellular differentiation medicine.medical_treatment Biochemistry Redox Signaling Dishevelled Neural Stem Cells medicine Human Neural Progenitor Cells Humans Calcium Signaling Molecular Biology Wnt Signaling Pathway beta Catenin Calcium signaling chemistry.chemical_classification Mitochondrial Metabolism biology Growth factor Wnt signaling pathway LRP5 Cell Differentiation Cell Biology Cell biology Wnt Pathway Mitochondria Wnt Proteins chemistry Reactive Oxygen Species (ROS) Catenin biology.protein Calcium Reactive Oxygen Species Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Dissociation of the Wnt/β-catenin pathway effector Dishevelled from its complex with nucleoredoxin is a redox-sensitive process, yet the ROS sources remain elusive. Results: Mitochondrial Ca2+ influx stimulates endogenous ROS production and mediates Wnt/β-catenin pathway activity. Conclusion: Ca2+-mediated ROS production modulates the signaling efficiency of the Wnt/β-catenin pathway. Significance: Metabolic states influence fundamental and developmental signaling to drive cell differentiation. 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 Ca2+ from the endoplasmic reticulum stores. Ca2+ subsequently accumulates in the mitochondria and triggers ROS production. The inhibition of mitochondrial Ca2+ 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 Ca2+-mediated ROS metabolic cues that fine-tune the efficiency of cell differentiation by modulating the extent of the Wnt/β-catenin signaling output. |
| Databáze: | OpenAIRE |
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