Reduction of mitochondrial protein mitoNEET [2Fe-2S] clusters by human glutathione reductase.
Reduction of mitochondrial protein mitoNEET [2Fe-2S] clusters by human glutathione reductase.
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DOI：
10.1016/j.freeradbiomed.2015.01.017
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发表时间：
2015-04
影响因子：
7.4
通讯作者：
Ding, Huangen
中科院分区：
文献类型：
--
作者：
Landry, Aaron P.;Cheng, Zishuo;Ding, Huangen
关键词：
人线粒体外膜蛋白mitoNEET是II型糖尿病药物吡格列酮新发现的靶点。在结构上，mitoNEET是一种同源二聚体，其中每个单体含有一个N-末端跨膜α螺旋和一个C-末端胞质结构域，其中N-末端跨膜α螺旋与线粒体外膜相连，C-末端胞质结构域含有一个氧化还原活性[2Fe-2S]簇。遗传学研究表明，mitoNEET在调节线粒体能量代谢中起着核心作用。然而，mitoNEET的具体功能在很大程度上仍然难以捉摸。在这里，我们发现，mitoNEET [2Fe-2S]簇可以有效地减少大肠杆菌硫氧还蛋白还原酶和谷胱甘肽还原酶的NADPH依赖性反应。纯化的人谷胱甘肽还原酶具有与E.大肠杆菌硫氧还蛋白还原酶和谷胱甘肽还原酶来还原mitoNEET [2Fe-2S]簇。然而，大鼠硫氧还蛋白还原酶（一种在催化中心含有硒代半胱氨酸的人类硫氧还蛋白还原酶同系物）对还原mitoNEET [2Fe-2S]簇的活性非常小或没有。N-乙基马来酰亚胺是一种有效的巯基修饰剂，可完全抑制人谷胱甘肽还原酶还原mitoNEET [2Fe-2S]簇，表明人谷胱甘肽还原酶催化中心的氧化还原活性二硫化物可能直接参与mitoNEET [2Fe-2S]簇的还原。进一步的研究表明，小鼠心脏细胞提取物中还原的mitoNEET [2Fe-2S]簇可以被过氧化氢可逆氧化而不破坏簇，这表明mitoNEET [2Fe-2S]簇可能发生氧化还原转变以调节线粒体中响应氧化信号的能量代谢。
Human mitochondrial outer membrane protein mitoNEET is a newly discovered target of type II diabetes drug pioglitazone. Structurally, mitoNEET is a homodimer with each monomer containing an N-terminal transmembrane alpha helix tethered to mitochondrial outer membrane and a C-terminal cytosolic domain hosting a redox active [2Fe-2S] cluster. Genetic studies have shown that mitoNEET has a central role in regulating energy metabolism in mitochondria. However, specific function of mitoNEET remains largely elusive. Here we find that the mitoNEET [2Fe-2S] clusters can be efficiently reduced by Escherichia coli thioredoxin reductase and glutathione reductase in an NADPH-dependent reaction. Purified human glutathione reductase has the same activity as E. coli thioredoxin reductase and glutathione reductase to reduce the mitoNEET [2Fe-2S] clusters. However, rat thioredoxin reductase, a human thioredoxin reductase homolog that contains selenocysteine in the catalytic center, has very little or no activity to reduce the mitoNEET [2Fe-2S] clusters. N-ethylmaleimide, a potent thiol modifier, completely inhibits human glutathione reductase to reduce the mitoNEET [2Fe-2S] clusters, indicating that the redox active disulfide in the catalytic center of human glutathione reductase may be directly involved in reducing the mitoNEET [2Fe-2S] clusters. Additional studies reveal that the reduced mitoNEET [2Fe-2S] clusters in mouse heart cell extracts can be reversibly oxidized by hydrogen peroxide without disruption of the clusters, suggesting that the mitoNEET [2Fe-2S] clusters may undergo redox transition to regulate energy metabolism in mitochondria in response to oxidative signals.
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影响因子：
10.5
作者：
Chen, Yi-Fan;Kao, Cheng-Heng;Tsai, Ting-Fen
通讯作者：
Tsai, Ting-Fen
影响因子：
5.6
作者：
Conlan, Andrea R.;Axelrod, Herbert L.;Paddock, Mark L.
通讯作者：
Paddock, Mark L.
影响因子：
4.8
作者：
Bertsch, Johannes;Parthasarathy, Anutthaman;Mueller, Volker
通讯作者：
Mueller, Volker
影响因子：
2.9
作者：
GRIFFITH, OW
通讯作者：
GRIFFITH, OW
DOI：
10.1073/pnas.1116369109
发表时间：
2012-02-07
影响因子：
11.1
作者：
Baxter, Elizabeth Leigh;Jennings, Patricia A.;Onuchic, Jose N.
通讯作者：
Onuchic, Jose N.