Intracellular labile iron

Abstract

Cells maintain organellar pools of “labile iron” (LI), despite its propensity for catalyzing the formation of reactive oxygen species. These pools are identifiable by iron-chelating probes and accessible to pharmacological agents. Cytosolic LI has been assumed to have a dual function: providing a rapidly adjustable source of iron for immediate metabolic utilization, and for sensing by iron-regulatory proteins (IRPs) that regulate iron uptake and compartmentalization via transferrin receptors and ferritin. However, it now appears that IRPs may respond both to fluctuations in LI per se and to secondary signals associated with redox-active species. Recent information also indicates that iron can be delivered to mitochondria via pathways that circumvent cytosolic LI, suggesting possible alternative mechanisms of cell iron mobilization and trafficking. We discuss the changing views of intracellular LI pools in relation to iron homeostasis and cellular distribution in physiological and pathological states.

Introduction

The existence of a cellular pool of metabolically available, labile iron (LI), has remained controversial. Firstly, its inherently transient nature, susceptibility to exchange between chemical ligands and to environment-sensitive redox conversions, have made it difficult to chemically quantify or even characterize. Secondly, the actual concept of cellular pools of LI might be considered counterintuitive, as it would entail the heavy cost of coping with continual iron-catalyzed generation of toxic reactive oxygen species (ROS). The development of iron-sensitive fluorescent probes has provided much evidence in favor of intracellular LI pools. Cytosolic LI is still portrayed as a key player in the cell iron-sensing machinery and hub of iron homeostasis (reviewed in Kakhlon & Cabantchik, 2002; Kruszewski, 2003). Yet, there remains considerable uncertainty about the mechanisms by which it affects iron-handling proteins and is in turn influenced by them. The notion of diffusible LI that is randomly bound to cellular ligands of variable affinities does not exclude the possibilities of escorted iron delivery to organelles and ensuing compartmentalization. The purpose of this review is to critically examine these evolving concepts and open questions, and point out new directions for investigating cellular LI.