TY - JOUR
T1 - Metal-ion transporter SLC39A8 is required for brain manganese uptake and accumulation
AU - Liu, Qingli
AU - Jenkitkasemwong, Supak
AU - Prami, Tamanna Afrin
AU - McCabe, Shannon Morgan
AU - Zhao, Ningning
AU - Hojyo, Shintaro
AU - Fukada, Toshiyuki
AU - Knutson, Mitchell D.
N1 - Funding Information:
We thank Drs Eduardo Candelario-Jalil and Changjun Yang (Department of Neuroscience, University of Florida) for technical assistance with isolating brain microvessels. Q. L. S. J. and M. D. K. conceptualization; Q. L. S. J. T. A. P. and M. D. K. investigation; Q. L. S. J. T. A. P. N. Z. and M. D. K. methodology; Q. L. S. J. T. A. P. and M. D. K. formal analysis; Q. L. and M. D. K. writing–original draft; Q. L. S. J. S. M. M. N. Z. S. H. T. F. and M. D. K. writing–review and editing; S. M. M. N. Z. S. H. and T. F. resources; S. J. visualization; M. D. K. funding acquisition; M. D. K. project administration; M. D. K. supervision. This work was supported by NIH R01 grants DK080706 (to M. D. K.) and DK123113 (to N. Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by NIH R01 grants DK080706 (to M. D. K.) and DK123113 (to N. Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - blood–brain barrier
KW - brain
KW - manganese
KW - SLC39A14
KW - SLC39A8
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U2 - 10.1016/j.jbc.2023.105078
DO - 10.1016/j.jbc.2023.105078
M3 - Article
C2 - 37482277
AN - SCOPUS:85168313708
SN - 0021-9258
VL - 299
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
M1 - 105078
ER -