A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease.
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease.
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DOI：
10.1016/j.nbd.2009.02.009
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发表时间：
2009-06
影响因子：
6.1
通讯作者：
Greenamyre JT
中科院分区：
文献类型：
--
作者：
Mastroberardino PG;Hoffman EK;Horowitz MP;Betarbet R;Taylor G;Cheng D;Na HM;Gutekunst CA;Gearing M;Trojanowski JQ;Anderson M;Chu CT;Peng J;Greenamyre JT
在帕金森病（PD）患者的黑质（SN）中最初描述铁积累超过80年后，导致这种现象的机制仍然未知。同样，铁是如何传递到细胞中的主要受体-线粒体和呼吸复合体-尚未阐明。在这里，我们报告了一种新的转铁蛋白/转铁蛋白受体2（Tf/TfR 2）介导的铁转运途径在SN多巴胺神经元的线粒体。我们发现，TfR 2有一个以前未表征的线粒体靶向序列，足以将蛋白质导入这些细胞器。重要的是，Tf/TfR 2途径可以将Tf结合的铁递送到线粒体和呼吸复合物I。该途径是氧化还原敏感的，Tf硫醇氧化成二硫化物诱导Tf释放高活性亚铁，这有助于自由基的产生。在PD的鱼藤酮模型中，Tf在多巴胺神经元中积累，其中大部分积累在线粒体中。这与SN中的铁沉积有关，类似于PD中发生的情况。在人SN中，TfR 2也存在于多巴胺神经元的线粒体中，并且在PD中，SN中的氧化Tf显著增加。因此，我们发现了一种新的线粒体铁转运系统，在PD中出错，这可能为治疗干预提供新的靶点。
More than 80 years after iron accumulation was initially described in the substantia nigra (SN) of Parkinson's disease (PD) patients, the mechanisms responsible for this phenomenon are still unknown. Similarly, how iron is delivered to its major recipients in the cell – mitochondria and the respiratory complexes – has yet to be elucidated. Here, we report a novel transferrin/transferrin receptor 2 (Tf/TfR2)-mediated iron transport pathway in mitochondria of SN dopamine neurons. We found that TfR2 has a previously uncharacterized mitochondrial targeting sequence that is sufficient to import the protein into these organelles. Importantly, the Tf/TfR2 pathway can deliver Tf bound iron to mitochondria and to the respiratory complex I as well. The pathway is redox-sensitive and oxidation of Tf thiols to disulfides induces release from Tf of highly reactive ferrous iron, which contributes to free radical production. In the rotenone model of PD, Tf accumulates in dopamine neurons, with much of it accumulating in the mitochondria. This is associated with iron deposition in SN, similar to what occurs in PD. In the human SN, TfR2 is also found in mitochondria of dopamine neurons, and in PD there is a dramatic increase of oxidized Tf in SN. Thus, we have discovered a novel mitochondrial iron transport system that goes awry in PD, and which may provide a new target for therapeutic intervention.
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影响因子：
6
作者：
Borie, C;Gasparini, F;Grandchamp, B
通讯作者：
Grandchamp, B
影响因子：
2.5
作者：
Dekker, MCJ;Giesbergen, PC;van Duijn, CM
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van Duijn, CM
影响因子：
3.5
作者：
Choo, YS;Johnson, GVW;Lesort, M
通讯作者：
Lesort, M
影响因子：
5.1
作者：
Huang, Xi-Ping;O'Brien, Peter J.;Templeton, Douglas M.
通讯作者：
Templeton, Douglas M.
影响因子：
3.3
作者：
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通讯作者：
Enns, Caroline A.