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.
Highlights
Iron plays a central role in a variety of essential cellular functions as oxygen transport and exchange, being the metal component of many intracellular enzymes
Iron is essential for insulin secretion [12,13], yet its accumulation is an important determinant of pancreatic islet inflammation and is considered a biomarker of diabetes risk and mortality [14]
Only PCBP2 can bind to the carrier systems DMT1 and FPN1 in an iron-dependent way [56,57]. Both PCBP1 and PCBP2 can deliver iron to ferritin, but only PCBP1 is fundamental in ferritinophagy, an iron recycling process [58] in which the iron-ferritin complex is captured by the nuclear receptor coactivator-4 (NCOA4) and directed into the autophagosome [59]
Summary
Iron plays a central role in a variety of essential cellular functions as oxygen transport and exchange, being the metal component of many intracellular enzymes. Its ability to react with oxygen makes it a toxic compound, able to generate reactive oxygen species (ROS) that can damage DNA, phospholipids and proteins It is of utmost importance, for both the cells and the organisms, to maintain iron homeostasis, ensuring iron supply and preventing accumulation of iron excess. ROS accumulation occurring in the presence of excess iron can induce oxidative damage of pancreatic beta-cells. Uptake of iron in beta-cells is performed by two different systems: a receptor-mediated transport for the transferrin-bound iron (TBI) and a non-transferrin-bound iron (NTBI) transport. NTBI uptake is mediated by the zinc transporter ZIP14 (SLC39A14), which localises to the plasma membrane of beta-cells, where iron loading is restricted. A role of L-type or T-type calcium channels seems unlikely due to the lack of iron overload in murine beta-cells expressing them [35]
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