Morphine-induced modulation of endolysosomal iron mediates upregulation of ferritin heavy chain in cortical neurons

Bradley Nash, Kevin Tarn, Elena Irollo, Jared Luchetta, Lindsay Festa, Peter Halcrow, Gaurav Datta, Jonathan D. Geiger, Olimpia Meucci

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by μ-opioid use. We have previously shown that morphine and other μ-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose dependently increased FHC protein levels in primary neurons through μ-opioid receptor (μOR) and Gαi-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, both in vitro and in vivo FHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on μOR and Gαi-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects.

Original languageEnglish (US)
Article numberENEURO.0237-19.2019
JournaleNeuro
Volume6
Issue number4
DOIs
StatePublished - Jul 1 2019

Keywords

  • Dendritic spine
  • Endolysosome
  • Ferritin
  • Morphine
  • Neuron
  • neuroHIV

ASJC Scopus subject areas

  • Neuroscience(all)

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    Nash, B., Tarn, K., Irollo, E., Luchetta, J., Festa, L., Halcrow, P., Datta, G., Geiger, J. D., & Meucci, O. (2019). Morphine-induced modulation of endolysosomal iron mediates upregulation of ferritin heavy chain in cortical neurons. eNeuro, 6(4), [ENEURO.0237-19.2019]. https://doi.org/10.1523/ENEURO.0237-19.2019