中国科学院上海生命科学研究院营养科学研究所王福俤博士研究组与美国密歇根大学的Haoxing Xu博士、波士顿儿童医院以及瑞典Linköping大学的科学家合作，首次阐明了TRPML1是一种二价铁离子(Fe2+)通道。研究成果《The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel》近期发表在《自然》杂志上。
TRPML1是TRP(transient receptor potential)离子通道蛋白，分布在细胞内体和溶酶体，在人类粘脂质累积病IV型(Mucolipidosis, ML4)患者中发现有突变。ML4是一种罕见的严重遗传性神经疾病，其主要临床表现为运动障碍、智力低下、视网膜变性和缺铁性贫血，且随着患者年龄增长症状会逐渐加重。以往研究推测，TRPML1是一种Ca2+通道，Ca2+代谢紊乱导致ML4发病。王福俤博士研究组及其合作者利用多种前沿生物学技术，包括放射性铁离子吸收定量测定、金属离子特异荧光成像以及细胞内体溶酶体膜片钳揭示TRPML1实际上是Fe2+通道。在酸性条件下，正常晚期内体和溶酶体中TRPML1具有非常强的泵出Fe2+的能力；而ML4突变的TRPML1蛋白却表现为泵出Fe2+的功能受到抑制或阻断。因此，细胞内铁离子转运障碍是导致ML4发病的真正分子机理。基于TRPML1在细胞内铁代谢中的重要作用，设计针对溶酶体靶向的铁螯合物可能会成为治疗ML4患者的新举措。“TRPML1是分布在细胞内体和溶酶体的二价铁离子通道”这一重要发现不仅极大地丰富和完善了细胞铁稳态调控理论体系，而且还对铁代谢相关疾病，包括癌症、糖尿病、神经退行性病变等的预防和治疗的研究开辟了新的途径。
王福俤研究组重点研究微量元素锌和铁的稳态调控机理，并通过多种生物学技术和实验体系筛选和鉴定新的金属离子转运相关基因。TRPML1是继Mon1a(Nature Genetics, 2007)和Sec15L1(Nature Genetics, 2005)之后王福俤博士独立或参与发现的第三个铁代谢调控新基因。目前，该研究组正与多家科研单位合作，继续对TRPML1导致ML4的分子机理进行深入研究。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
