Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction

Abstract

Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.

Keywords: Iron metabolism; beta-cell function; diabetes; reactive oxygen species.

Figure 1

Overview of iron homeostasis in beta-cells. (a) Iron uptake in beta-cells is mediated by endocytosis of the transferrin-transferrin receptor complex and its release from endosomes by the divalent metal ion transporter DMT1. As non-transferrin-bound iron (NTBI), it can also be imported by the zinc transporter ZIP14 transporter. Being toxic as a free ion, Fe²⁺ is then readily distributed for storage, bound to ferritin or for utilisation by chaperoning proteins as PCBPs and lipocalin. Iron efflux is mediated by ferroportin, a process regulated by hepcidin and hephaestin. LIP: labile iron pool. (b) Within the cell, the major site of utilisation is the mitochondria, where the ion is transported via DMT1 and mitoferrin (Mfrn1, Mfrn2) and inserted into heme and Fe/S cluster prosthetic groups. Mitochondria iron efflux is probably mediated by the ATP-binding cassette (ABC) transporter ABCB7. (c) Beta-cells, together with insulin, release IAPP and hepcidin, involved in a possible modulation of iron metabolism by an autocrine mechanism, via regulation of ferroportin.

Figure 2

Iron is relevant for beta-cell function and preservation. Beta-cell iron homeostasis is under the control of the iron regulatory proteins (IRPs). Fe-S-cluster proteins are necessary for the correct processing and synthesis of insulin. The Fe-S cluster enzyme CDKAL1 is responsible for the adenosine methylthiolation in the tRNA for lysine, a modification required for the pro-insulin translational fidelity in pancreatic beta-cells. CDKAL1 is under the control of IRP2 (1). Iron is also essential for the metabolic coupling of insulin release: obligatory steps of the tricarboxylic acid (TCA) cycle are mediated by iron-dependent enzymes, and Fe-S cluster proteins are part of the respiratory chain complexes, allowing the synthesis of ATP (2). As a co-factor of the prolyl and asparaginyl hydroxylase (PHD), iron controls the degradation of hypoxia-inducible factor HIF-1α factor, influencing beta-cell response to hypoxia (3). Iron is also necessary to control inflammation, as PHD hydroxylates and inactivates the inhibitor of κB kinase (IKKb), an important upstream regulator of nuclear factor (NF)-kB (NF-kB) pathway, the major pro-inflammatory pathway in beta-cells (4).

Figure 3

Iron-mediated toxic effects in beta-cells. Iron-mediated beta-cell toxicity is mainly due to reactive oxygen species (ROS) accumulation through Fenton’s reaction. ROS excess determines DNA, lipid and protein oxidation that causes mitochondrial damage, leading to insulin release and apoptosis (1). ROS also influence the activity of the pancreatic and duodenal homeobox 1 (PDX1) and V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), critical transcription factors for the control of insulin gene expression (2). Iron can induce beta-cell loss also through ferroptosis, a non-apoptotic cell death mechanism characterised by lipid ROS accumulation due to glutathione (GSH) depletion and consequent glutathione peroxidase-4 (GPX4) inhibition (3).