title: Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway.
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.
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hatori
authors.affiliation: Department of Neuroscience, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, Maryland 21205, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Eri
authors.initials: E
authors.lastname: Furukawa
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Nesrin M
authors.initials: NM
authors.lastname: Hasan
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Chin-Nung
authors.initials: CN
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, Maryland 21205, USA.
authors.forename: Shanthini
authors.initials: S
authors.lastname: Sockanathan
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, 725 N. Wolfe street, Baltimore, 21205 Maryland, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D019760:Amidine-Lyases / Q000378:metabolism*; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002642:Chick Embryo; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D003600:Cytosol; D018274:Electroporation; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D056511:Metallochaperones / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D018832:Molecular Chaperones; D009249:NADP / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D055571:Secretory Pathway; D013054:Spectrophotometry, Atomic; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000378:metabolism
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D009249:NADP; D003300:Copper; D006899:Mixed Function Oxygenases; C544787:PAM protein, human; D000251:Adenosine Triphosphatases; D019760:Amidine-Lyases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D005978:Glutathione; D019803:Glutathione Disulfide