Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders.
Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders.
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DOI：
10.1038/s41598-018-21464-0
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发表时间：
2018-02-16
影响因子：
4.6
通讯作者：
Seo YA
中科院分区：
文献类型：
--
作者：
Choi EK;Nguyen TT;Gupta N;Iwase S;Seo YA
SLC39A8 编码 ZIP8，一种二价金属离子转运蛋白。 SLC39A8 基因突变与先天性糖基化 II 型疾病和 Leigh 综合征有关。值得注意的是，患有这两种疾病的患者都表现出严重的锰（Mn）缺乏。人类 SLC39A8 (hSLC39A8) 的细胞功能以及该蛋白突变导致人类疾病的机制尚不清楚。在此，我们表明hSLC39A8介导细胞对54Mn的摄取，并且其表达受Mn调节。虽然野生型 hSLC39A8 的表达增加了 54Mn 摄取活性，但与疾病相关的突变消除了转运蛋白介导细胞摄取 Mn 的能力，从而提供了与严重 Mn 缺乏的因果关系。所有突变体均未能定位于细胞表面并保留在内质网内。有趣的是，CDG II 型和 Leigh 综合征的 hSLC39A8 突变体的表达降低了线粒体 54Mn 水平和 Mn 依赖性线粒体超氧化物歧化酶 MnSOD 的活性，进而增加了氧化应激。野生型 hSLC39A8 的表达（而非疾病相关突变体）促进线粒体功能。此外，功能丧失分析进一步证实了 hSLC39A8 在介导 Mn 摄取和线粒体功能中的关键作用。我们的结果提供了与 hSLC39A8 突变相关的疾病的潜在致病机制。
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.
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影响因子：
10.6
作者：
Jeong, Jeeyon;Eide, David J.
通讯作者：
Eide, David J.
影响因子：
9.8
作者：
Park, Julien H.;Hogrebe, Max;Marquardt, Thorsten
通讯作者：
Marquardt, Thorsten
影响因子：
3.3
作者：
Mukhopadhyay S;Bachert C;Smith DR;Linstedt AD
通讯作者：
Linstedt AD
DOI：
10.1023/a:1020602222808
发表时间：
1999-08-01
期刊：
JOURNAL OF PROTEIN CHEMISTRY
影响因子：
--
作者：
Jabalquinto, AM;Laivenieks, M;Cardemil, E
通讯作者：
Cardemil, E
影响因子：
3.4
作者：
Roth, JA;Horbinski, C;Garrick, MD
通讯作者：
Garrick, MD