中國科學(xué)院上海生命科學(xué)研究院營養(yǎng)科學(xué)研究所王福俤博士研究組與美國密歇根大學(xué)的Haoxing Xu博士、波士頓兒童醫(yī)院以及瑞典Linköping大學(xué)的科學(xué)家合作,，首次闡明了TRPML1是一種二價鐵離子(Fe2+)通道。研究成果《The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel》近期發(fā)表在《自然》雜志上,。
TRPML1是TRP(transient receptor potential)離子通道蛋白,，分布在細(xì)胞內(nèi)體和溶酶體，在人類粘脂質(zhì)累積病IV型(Mucolipidosis, ML4)患者中發(fā)現(xiàn)有突變,。ML4是一種罕見的嚴(yán)重遺傳性神經(jīng)疾病，其主要臨床表現(xiàn)為運動障礙,、智力低下,、視網(wǎng)膜變性和缺鐵性貧血，且隨著患者年齡增長癥狀會逐漸加重,。以往研究推測,，TRPML1是一種Ca2+通道，Ca2+代謝紊亂導(dǎo)致ML4發(fā)病,。王福俤博士研究組及其合作者利用多種前沿生物學(xué)技術(shù)，包括放射性鐵離子吸收定量測定,、金屬離子特異熒光成像以及細(xì)胞內(nèi)體溶酶體膜片鉗揭示TRPML1實際上是Fe2+通道,。在酸性條件下,，正常晚期內(nèi)體和溶酶體中TRPML1具有非常強的泵出Fe2+的能力,；而ML4突變的TRPML1蛋白卻表現(xiàn)為泵出Fe2+的功能受到抑制或阻斷。因此,，細(xì)胞內(nèi)鐵離子轉(zhuǎn)運障礙是導(dǎo)致ML4發(fā)病的真正分子機理,。基于TRPML1在細(xì)胞內(nèi)鐵代謝中的重要作用,，設(shè)計針對溶酶體靶向的鐵螯合物可能會成為治療ML4患者的新舉措。“TRPML1是分布在細(xì)胞內(nèi)體和溶酶體的二價鐵離子通道”這一重要發(fā)現(xiàn)不僅極大地豐富和完善了細(xì)胞鐵穩(wěn)態(tài)調(diào)控理論體系,，而且還對鐵代謝相關(guān)疾病,，包括癌癥,、糖尿病,、神經(jīng)退行性病變等的預(yù)防和治療的研究開辟了新的途徑,。
王福俤研究組重點研究微量元素鋅和鐵的穩(wěn)態(tài)調(diào)控機理，并通過多種生物學(xué)技術(shù)和實驗體系篩選和鑒定新的金屬離子轉(zhuǎn)運相關(guān)基因,。TRPML1是繼Mon1a(Nature Genetics, 2007)和Sec15L1(Nature Genetics, 2005)之后王福俤博士獨立或參與發(fā)現(xiàn)的第三個鐵代謝調(diào)控新基因,。目前，該研究組正與多家科研單位合作,，繼續(xù)對TRPML1導(dǎo)致ML4的分子機理進行深入研究,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature advance online publication 14 September 2008 | doi:10.1038/nature07311
The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
Xian-Ping Dong1, Xiping Cheng1, Eric Mills1, Markus Delling2, Fudi Wang3, Tino Kurz4 & Haoxing Xu1
1 The Department of Molecular, Cellular, and Developmental Biology, The University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA
2 The Department of Cardiology, Children's Hospital Boston, Enders 1350, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
3 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
4 Department of Pharmacology, Faculty of Health Science, University of Link?ping, S-58185 Link?ping, Sweden
TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins1,2, 3. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4)4, 5. ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration6, 7, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+-bound transferrin receptors6, or after lysosomal degradation of ferritin–iron complexes and autophagic ingestion of iron-containing macromolecules6, 8, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors6, 9. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+transport protein9. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1 -/- ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe2+ levels and an accumulation of lipofuscin-like molecules in TRPML1 -/- cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients.
