Identification of human genes of iron homeostasis

1)铁很难。它是几乎所有生物体的必需营养素；然而，在我们富氧的大气中，它主要以铁（Fe+3）的状态存在，这在支持生命的水环境中几乎是不溶的。大多数生物系统利用铁，铁+2形式，这是容易溶解的，但也高度化学反应。尽管这种化学反应性在酶或携氧分子中以铁辅助因子的形式存在时非常有用，但无伴侣铁也可能对细胞具有高度毒性，因为它催化活性氧的形成，而活性氧会破坏脂质、蛋白质和核酸(1)。对许多生物来说，低铁的生物利用度限制了它们的生长。长期以来，人类一直在与膳食铁不足作斗争，因为世界上大多数人赖以生存的植物性饮食往往铁含量较低(2)。因此，毫不奇怪，人类已经进化到非常有效地利用饮食和身体的铁储备。我们对铁的再利用是如此高效，以至于人类没有有效的方法来清除体内多余的铁。没有排泄铁的方法，我们的铁摄取系统必须精确调节，以满足不断变化的代谢需求，避免铁过载。虽然一个健康的人可以活100年而不缺铁或铁超载，但许多疾病状态都与这种平衡的破坏有关。与铁超载相关的疾病既有遗传性的，也有获得性的，由内在的铁运输失调或由红细胞输注形式的医源性铁负荷引起(3)。过量的铁通常积聚在网状内皮系统的细胞中，但严重的铁超载会影响实质细胞，特别是肝、心和肾的细胞。这些铁可以通过简单的干预措施去除，如静脉切开术，但在因贫血而不能进行静脉切开术的情况下，必须采用药物手段。目前有三种药物被批准作为螯合剂用于治疗铁超载：去铁胺、去铁素和去铁素(4)。每种方法都有其优点和局限性。Ekaputri等人在本期PNAS上讨论了扁树醇的生物活性和潜在的治疗用途，扁树醇是一种小的植物源分子，在亚洲传统医学中使用，也有可能在铁过载的情况下调动铁(5)。

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.