Shvartsman Maya, Kikkeri Raghavendra, Shanzer Abraham, Cabantchik Z Ioav
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Safra Campus at Givat Ram, Jerusalem, Israel.
Am J Physiol Cell Physiol. 2007 Oct;293(4):C1383-94. doi: 10.1152/ajpcell.00054.2007. Epub 2007 Aug 1.
Non-transferrin-bound iron, commonly found in the plasma of iron-overloaded individuals, permeates into cells via pathways independent of the transferrin receptor. This may lead to excessive cellular accumulation of labile iron followed by oxidative damage and eventually organ failure. Mitochondria are the principal destination of iron in cells and a primary site of prooxidant generation, yet their mode of acquisition of iron is poorly understood. Using fluorescent probes sensitive to iron or to reactive oxygen species, targeted to cytosol and/or to mitochondria, we traced the ingress of labile iron into these compartments by fluorescence microscopy and quantitative fluorimetry. We observed that 1) penetration of non-transferrin-bound iron into the cytosol and subsequently into mitochondria occurs with barely detectable delay and 2) loading of the cytosol with high-affinity iron-binding chelators does not abrogate iron uptake into mitochondria. Therefore, a fraction of non-transferrin-bound iron acquired by cells reaches the mitochondria in a nonlabile form. The physiological role of occluded iron transfer might be to confer cells with a "safe and efficient cytosolic iron corridor" to mitochondria. However, such a mechanism might be deleterious in iron-overload conditions, because it could lead to surplus accumulation of iron in these critical organelles.
非转铁蛋白结合铁常见于铁过载个体的血浆中，它通过不依赖转铁蛋白受体的途径渗透进入细胞。这可能导致不稳定铁在细胞内过度积累，继而引发氧化损伤并最终导致器官衰竭。线粒体是细胞中铁的主要归宿以及促氧化剂产生的主要部位，然而其获取铁的方式却鲜为人知。我们使用对铁或活性氧敏感的荧光探针，将其靶向胞质溶胶和/或线粒体，通过荧光显微镜和定量荧光测定法追踪不稳定铁进入这些区室的过程。我们观察到：1）非转铁蛋白结合铁进入胞质溶胶并随后进入线粒体的过程几乎没有可检测到的延迟；2）用高亲和力铁结合螯合剂装载胞质溶胶并不能消除铁进入线粒体的现象。因此，细胞获取的一部分非转铁蛋白结合铁以非不稳定形式到达线粒体。封闭性铁转运的生理作用可能是赋予细胞一条通向线粒体的“安全且高效的胞质溶胶铁通道”。然而，这样一种机制在铁过载情况下可能是有害的，因为它可能导致这些关键细胞器中铁的过量积累。
