Abstract
Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.
Highlights
Iron is a transition metal with critical biological functions [1]
The activity of mitochondrial aconitase, an enzyme catalyzing conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle, depends on a 4Fe-4S cluster in its active site
Cellular iron uptake involves binding of transferrin to TfR1 on the plasma membrane, which is followed by internalization of the complex via endocytosis, release of iron from the acidified endosome and exit to the cytosol via DMT1
Summary
Iron is a transition metal with critical biological functions [1]. In mammals, most of body iron is present in hemoglobin of red blood cells and mediates oxygen transport. Cell culture experiments showed that iron depletion inhibits mitochondrial aconitase, and other enzymes of the TCA cycle such as citrate synthase, isocitrate dehydrogenase and succinate dehydrogenase [2]. This decreases formation of NADH and ATP, and reduces oxygen consumption in the electron transport chain. Iron intake triggers hepcidin induction in response to increased iron saturation of plasma transferrin and secretion of BMP6 (bone morphogenetic protein 6) from liver sinusoidal endothelial cells [14] (Figure 1). Pharmacological inhibition of the SMAD pathway [17,18], or genetic inactivation of some of its components [19,20] attenuated inflammatory hepcidin responses
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