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Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway

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  • Yuta Hatori

    (Johns Hopkins University, School of Medicine
    Present address: Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami-Ku, Hiroshima 731-0153, Japan)

  • Ye Yan

    (Johns Hopkins University, School of Medicine
    Present address: Center for Molecular Medicine, National heart, lung and blood Institute (NHLBI), NIH Building 10-CRC Room 5-3288, 10 Center Drive, Bethesda, Maryland 20892, USA)

  • Katharina Schmidt

    (Johns Hopkins University, School of Medicine)

  • Eri Furukawa

    (Johns Hopkins University, School of Medicine
    Present address: The Department of Genetics, The University of Texas MD Anderson Cancer Center, Unit1010, 1515 Holcombe Blvd. Houston, Texas 77030, USA)

  • Nesrin M. Hasan

    (Johns Hopkins University, School of Medicine)

  • Nan Yang

    (Johns Hopkins University, School of Medicine)

  • Chin-Nung Liu

    (Johns Hopkins University, School of Medicine
    Present address: National Yang-Ming University, School of Medicine, Faculty of Medicine, No. 155, Sec. 2, Li-Nong Street, Pei-Tou, Taipei 112, Taiwan)

  • Shanthini Sockanathan

    (Johns Hopkins University, School of Medicine)

  • Svetlana Lutsenko

    (Johns Hopkins University, School of Medicine)

Abstract

Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site. Concomitantly, expression of Atox1 and its partner, a copper transporter ATP7A, is upregulated. These events produce a higher flux of copper through the secretory pathway that balances copper in the cytosol and increases supply of the cofactor to copper-dependent enzymes, expression of which is elevated in differentiated neurons. Direct link between glutathione oxidation and copper compartmentalization allows for rapid metabolic adjustments essential for normal neuronal function.

Suggested Citation

  • Yuta Hatori & Ye Yan & Katharina Schmidt & Eri Furukawa & Nesrin M. Hasan & Nan Yang & Chin-Nung Liu & Shanthini Sockanathan & Svetlana Lutsenko, 2016. "Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10640
    DOI: 10.1038/ncomms10640
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