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Sci Rep. 2018 Feb 16;8(1):3163. doi: 10.1038/s41598-018-21464-0.

Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders.

Author information

1
Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
2
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA. youngseo@umich.edu.

Abstract

SLC39A8 encodes ZIP8, a divalent metal ion transporter. Mutations in the SLC39A8 gene are associated with congenital disorder of glycosylation type II and Leigh syndrome. Notably, affected patients with both disorders exhibited severe manganese (Mn) deficiency. The cellular function of human SLC39A8 (hSLC39A8) and the mechanisms by which mutations in this protein lead to human diseases are unclear. Herein, we show that hSLC39A8 mediates 54Mn uptake by the cells, and its expression is regulated by Mn. While expression of wild-type hSLC39A8 increased 54Mn uptake activity, disease-associated mutations abrogated the ability of the transporter to mediate Mn uptake into the cells, thereby providing a causal link to severe Mn deficiency. All mutants failed to localize on the cell surface and were retained within the endoplasmic reticulum. Interestingly, expression of hSLC39A8 mutants of both CDG type II and Leigh syndrome reduced mitochondrial 54Mn levels and activity of Mn-dependent mitochondrial superoxide dismutase MnSOD, and in turn increased oxidative stress. The expression of wild-type hSLC39A8, but not the disease-associated mutants, promoted mitochondrial functions. Moreover, loss of function analyses further corroborate hSLC39A8's critical role in mediating Mn uptake and mitochondrial function. Our results provide a potential pathogenic mechanism of diseases that are associated with hSLC39A8 mutations.

PMID:
29453449
PMCID:
PMC5816659
DOI:
10.1038/s41598-018-21464-0
[Indexed for MEDLINE]
Free PMC Article

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