Metal-ion transporter SLC39A8 is required for brain manganese uptake and accumulation

Qingli Liu, Supak Jenkitkasemwong, Tamanna Afrin Prami, Shannon Morgan McCabe, Ningning Zhao, Shintaro Hojyo, Toshiyuki Fukada, Mitchell D. Knutson

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Manganese (Mn) is an essential nutrient, but is toxic in excess. Whole-body Mn levels are regulated in part by the metal-ion influx transporter SLC39A8, which plays an essential role in the liver by reclaiming Mn from bile. Physiological roles of SLC39A8 in Mn homeostasis in other tissues, however, remain largely unknown. To screen for extrahepatic requirements for SLC39A8 in tissue Mn homeostasis, we crossed Slc39a8-inducible global-KO (Slc39a8 iKO) mice with Slc39a14 KO mice, which display markedly elevated blood and tissue Mn levels. Tissues were then analyzed by inductively coupled plasma-mass spectrometry to determine levels of Mn. Although Slc39a14 KO; Slc39a8 iKO mice exhibited systemic hypermanganesemia and increased Mn loading in the bone and kidney due to Slc39a14 deficiency, we show Mn loading was markedly decreased in the brains of these animals, suggesting a role for SLC39A8 in brain Mn accumulation. Levels of other divalent metals in the brain were unaffected, indicating a specific effect of SLC39A8 on Mn. In vivo radiotracer studies using 54Mn in Slc39a8 iKO mice revealed that SLC39A8 is required for Mn uptake by the brain, but not most other tissues. Furthermore, decreased 54Mn uptake in the brains of Slc39a8 iKO mice was associated with efficient inactivation of Slc39a8 in isolated brain microvessels but not in isolated choroid plexus, suggesting SLC39A8 mediates brain Mn uptake via the blood–brain barrier. These findings establish SLC39A8 as a candidate therapeutic target for mitigating Mn uptake and accumulation in the brain, the primary organ of Mn toxicity.

Original languageEnglish (US)
Article number105078
JournalJournal of Biological Chemistry
Volume299
Issue number8
DOIs
StatePublished - Aug 2023

Keywords

  • SLC39A14
  • SLC39A8
  • blood–brain barrier
  • brain
  • manganese

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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