Non-transferrin-bound iron reaches mitochondria by a chelator-inaccessible mechanism: biological and clinical implications.
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.
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Safra Campus at Givat Ram, Jerusalem, Israel.
Maya
M
Shvartsman
Raghavendra
R
Kikkeri
Abraham
A
Shanzer
Z Ioav
ZI
Cabantchik
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005470:Fluorometry; D006835:Hydrazones / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D012235:Rhodamines / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014168:Transferrin / Q000378:metabolism
D000447:Aldehydes; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006835:Hydrazones; D007502:Iron Chelating Agents; D012235:Rhodamines; D014168:Transferrin; C083098:calcein green; C449922:rhodamine B-((1,10-phenanthrolin-5-yl)aminocarbonyl)benzyl ester; C413684:salicylaldehyde isonicotinoyl hydrazone; D004533:Egtazic Acid; C058180:5,5'-dimethyl-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate; D007501:Iron; D003676:Deferoxamine