Li Liangtao, Miao Ren, Jia Xuan, Ward Diane M, Kaplan Jerry
From the Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132.
From the Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132
J Biol Chem. 2014 Jun 13;289(24):17132-41. doi: 10.1074/jbc.M114.574723. Epub 2014 May 5.
Mmt1 and Mmt2 are highly homologous yeast members of the cation diffusion facilitator transporter family localized to mitochondria. Overexpression of MMT1/2 led to changes in cellular metal homeostasis (increased iron sensitivity, decreased cobalt sensitivity, increased sensitivity to copper), oxidant generation, and increased sensitivity to H2O2. The phenotypes due to overexpression of MMT1&2 were similar to that seen in cells with deletions in MRS3 and MRS4, genes that encode the mitochondrial iron importers. Overexpression of MMT1&2 resulted in induction of the low iron transcriptional response, similar to that seen in Δmrs3Δmr4 cells. This low iron transcriptional response was suppressed by deletion of CCC1, the gene that encodes the vacuolar iron importer. Measurement of the activity of the iron-dependent gentisate 1,2-dioxygenase from Pseudaminobacter salicylatoxidans expressed in yeast cytosol, showed that changes in Mmt1/2 levels affected cytosol iron concentration even in the absence of Ccc1. Overexpression of MMT1 resulted in increased cytosolic iron whereas deletion of MMT1/MMT2 led to decreased cytosolic iron. These results support the hypothesis that Mmt1/2 function as mitochondrial iron exporters.
Mmt1和Mmt2是定位在线粒体上的阳离子扩散促进剂转运蛋白家族中高度同源的酵母成员。MMT1/2的过表达导致细胞金属稳态发生变化（铁敏感性增加、钴敏感性降低、对铜的敏感性增加）、氧化剂生成以及对过氧化氢的敏感性增加。MMT1和MMT2过表达所导致的表型与线粒体铁输入蛋白编码基因MRS3和MRS4缺失的细胞中观察到的表型相似。MMT1和MMT2的过表达导致低铁转录反应的诱导，类似于在Δmrs3Δmr4细胞中观察到的情况。这种低铁转录反应被编码液泡铁输入蛋白的基因CCC1的缺失所抑制。对在酵母细胞质中表达的来自水杨酸盐氧化假氨基杆菌的铁依赖性龙胆酸盐1,2-双加氧酶活性的测量表明，即使在没有Ccc1的情况下，Mmt1/2水平的变化也会影响细胞质铁浓度。MMT1的过表达导致细胞质铁增加，而MMT1/MMT2的缺失导致细胞质铁减少。这些结果支持了Mmt1/2作为线粒体铁输出蛋白发挥作用的假说。
