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

Yuta Hatori, Ye Yan, Katharina Schmidt, Eri Furukawa, Nesrin M. Hasan, Nan Yang, Chin-Nung Liu, Shanthini Sockanathan and Svetlana Lutsenko ()
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Yuta Hatori: Johns Hopkins University, School of Medicine
Ye Yan: Johns Hopkins University, School of Medicine
Katharina Schmidt: Johns Hopkins University, School of Medicine
Eri Furukawa: Johns Hopkins University, School of Medicine
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
Shanthini Sockanathan: Johns Hopkins University, School of Medicine
Svetlana Lutsenko: Johns Hopkins University, School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10640

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