Identification of human genes of iron homeostasis

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

1)Iron is difficult. It is an essential nutrient for almost every organism; yet, in our oxygen-rich atmosphere, it largely exists in the ferric, Fe+3 state, which is practically insoluble in the aqueous milieu that supports life. Most biological systems utilize the ferrous, Fe+2 form, which is readily soluble but also highly chemically reactive. Although this chemical reactivity is very useful when present in the form of an iron cofactor in an enzyme or oxygen-carrying molecule, unchaperoned iron can also be highly toxic to cells because it catalyzes the formation of reactive oxygen species that can damage lipids, proteins, and nucleic acids (1). For many organisms, low iron bioavailability limits growth. Humans have long struggled with dietary iron insufficiency because the plant-based diets that sustain most of the peoples of the world tend to be low in iron (2). Thus, it is unsurprising that humans have evolved to be very efficient in their utilization of dietary and bodily reservoirs of iron. We are so efficient in iron reutilization that humans express no effective means of ridding the body of excess iron. Without a means to excrete iron, our systems of iron uptake must be precisely regulated to meet changing metabolic needs and avoid iron overload. Although a healthy human can live for 100 years without developing iron deficiency or iron overload, many disease states are associated with disruption of this balance. Disorders associated with iron overload are both inherited and acquired and caused by intrinsically dysregulated iron trafficking or by iatrogenic iron loading in the form of red blood cell transfusions (3). Excess iron typically accumulates in cells of the reticuloendothelial system, but in severe iron overload parenchymal cells, especially of the liver, heart and kidney can be affected. These iron stores can be removed by simple interventions, such as phlebotomy, but pharmacologic means are necessary where phlebotomy is not tolerated due to anemia. There are three drugs currently approved for use as chelators to treat iron overload: deferoxamine, deferiprone, and deferasirox (4). Each has its advantages and limitations. Ekaputri, et al. discuss in this issue of PNAS the biological activity and potential therapeutic use of hinokitiol, a small, plant-derived molecule used in traditional Asian medicine that also has the potential to mobilize iron in the setting of iron overload (5). 2) Iron is an essential nutrient that forms cofactors required for the activity of hundreds of cellular proteins. However, iron can be toxic and must be precisely managed. Poly r(C) binding protein 1 (PCBP1) is an essential, multifunctional protein that binds both iron and nucleic acids, regulating the fate of both. As an iron chaperone, PCBP1 binds cytosolic iron and delivers it to iron enzymes for activation and to ferritin for storage. Mice deleted for PCBP1 in the liver exhibit dysregulated iron balance, with lower levels of liver iron stores and iron enzymes, but higher levels of chemically-reactive iron. Unchaperoned iron triggers the formation of reactive oxygen species, leading to lipid peroxidation and ferroptotic cell death. Hepatic PCBP1 deletion produces chronic liver disease in mice, with steatosis, triglyceride accumulation, and elevated plasma ALT levels. Human and mouse models of fatty liver disease are associated with mitochondrial dysfunction. Here we show that, although deletion of PCBP1 does not affect mitochondrial iron balance, it does affect mitochondrial function. PCBP1 deletion affected mitochondrial morphology and reduced levels of respiratory complexes II and IV, oxygen consumption, and ATP production. Depletion of mitochondrial lipids cardiolipin and coenzyme Q, along with reduction of mitochondrial oxygen consumption, were the first manifestations of mitochondrial dysfunction. Although dietary supplementation with vitamin E ameliorated the liver disease in mice with hepatic PCBP1 deletion, supplementation with coenzyme Q was required to fully restore mitochondrial lipids and function. In conclusion, our studies indicate that mitochondrial function can be restored in livers subjected to ongoing oxidative damage from unchaperoned iron by supplementation with coenzyme Q, a mitochondrial lipid essential for respiration that also functions as a lipophilic radical-trapping agent.