Hemojuvelin: a supposed role in iron metabolism one year after its discovery

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.     

Mitochondrial uncoupling protein 3 and its role in cardiac- and skeletal muscle metabolism

Uncoupling protein 3 (UCP3), is primarily expressed in skeletal muscle mitochondria and has been suggested to be involved in mediating energy expenditure via uncoupling, hereby dissipating the mitochondrial proton gradient necessary for adenosine triphosphate (ATP) synthesis. Although some studies support a role for UCP3 in energy metabolism, other studies pointed towards a function in fatty acid metabolism. Thus, the protein is up regulated or high when fatty acid supply to the mitochondria exceeds the capacity to oxidize fatty acids and down regulated or low when oxidative capacity is high or improved.

Irrespective of the exact operating mechanism, UCP3 seems to protect mitochondria against lipid-induced oxidative stress, which makes this protein a potential player in the development of type 2 diabetes mellitus. Next to skeletal muscle, UCP3 is also expressed in cardiac muscle where its role is relatively unexplored. Interestingly, energy deficiency in cardiac muscle is associated to heart failure and UCP3 might contribute to this energy deficiency. It has been suggested that UCP3 decreases energy status via uncoupling of mitochondrial respiration, but the available data does not provide a unified answer. In fact, the results obtained regarding cardiac UCP3 are very similar as in skeletal muscle, implying that its physiological function can be extrapolated. Therefore, cardiac UCP3 can just as well serve to protect the heart against lipid-induced oxidative stress, similar to the function described for skeletal muscle UCP3. The present review will deal with the available literature on both skeletal muscle- and cardiac UCP3 to elucidate its physiological function in these tissues.     

FcgammaRIIB as a modulator of autoimmune disease susceptibility

Antibodies are secreted to recognize and in some cases directly neutralize pathogens. Another important means by which they are essential components of the immune system is through binding to Fc receptors. Effector responses triggered by antibody binding of Fc receptors affect a host of important cellular responses such as phagocytosis, inflammatory cytokine release, antigen presentation, and regulation of humoral responses. A crucial check on this antibody-mediated signal is through the inhibitory receptor, FcgammaRIIB. In this review we discuss how dysregulation of FcgammaRIIB can result in a lowered threshold for autoimmunity in mice and humans. We close with a discussion of the potential for applying these findings to immunotherapy.     

Recent advance in the understanding of iron metabolism and its role on host defense]

Iron is an essential trace element for human beings, but at the same time, it is toxic for us to generate free radicals because of its high reactivity to molecular oxygen. Therefore, iron metabolism is tightly regulated. Recently, hepcidin, a peptide hormone secreted by hepatocytes in response to iron overload and inflammation, has been identified to be a predominant negative regulator of iron absorption in the duodenum and iron release from tissue macrophages. The discovery of hepcidin unexpectedly revealed the link between iron metabolism and host defense. Here we describe recent advance in our understanding on the regulation of iron metabolism, including our findings and discuss its relationship to various diseases.     

Complement in multiple sclerosis: its role in disease and potential as a biomarker

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system with a poorly defined and complex immunopathogenesis. Although initiated by reactive T cells, persistent inflammation is evident throughout the disease course. A contribution from complement has long been suspected, based on the results of pathological and functional studies which have demonstrated complement activation products in MS brain and biological fluids. However, the extent and nature of complement activation and its contribution to disease phenotype and long‐term outcome remain unclear. Furthermore, functional polymorphisms in components and regulators of the complement system which cause dysregulation, and are known to contribute to other autoimmune inflammatory disorders, have not been investigated to date in MS in any detail. In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS. We also evaluate the potential of complement components and regulators and their polymorphic variants as biomarkers of disease, and suggest appropriate directions for future research.     

铁代谢及铁死亡在心肌病中的作用及调控机制研究进展

心肌细胞代谢及死亡方式是心肌病的重要病理生理学基础。许多研究提示,铁代谢紊乱是心肌病发生发展的关键环节之一。铁是人体重要生理功能所必需的矿物质,参与细胞呼吸、脂质代谢以及蛋白质合成;在病理条件下,铁蓄积诱导的毒性作用可破坏心肌细胞稳态和活力,导致细胞死亡,即铁死亡。过量的铁则通过芬顿反应诱导过氧化物生成,造成心肌细胞功能损害。因此,铁死亡在调控心肌病的发生及发展过程中具有重要意义。本文总结了铁代谢及铁死亡在心肌病中的病理生理改变及其调控机制,深刻认识铁代谢及铁死亡的调控靶点将为心肌病防治开辟新途径。     

脑铁代谢紊乱与阿尔茨海默病

脑内铁代谢的异常和其所致的氧化应激与阿尔茨海默病(Alzheimer'sdisease,AD)的发病有关。AD是常见于老年人的一种神经退行性疾病,其特征性的病理改变主要是脑内神经细胞外β-淀粉样蛋白(β-amyloid,Aβ)的沉积形成老年斑(senile plague,SP)、胞内神经原纤维缠结(neurofibrillary tangles,NFTs)和胆碱能神经元丢失。研究证实,在普通老年人和AD患者脑内有铁沉积增多的趋势,且铁等过渡金属离子与APP、Aβ和Tau蛋白密切相关,提示铁可能参与了AD的发病和进展等病理生理过程。因此,深入探讨铁在AD发病中可能的作用,有利于了解AD的发病机制,从而为AD疾病的治疗提供新的靶点。     

Mitochondrial energy metabolism plays a critical role in the cardioprotection afforded by intermittent hypobaric hypoxia

Intermittent hypobaric hypoxia (IHH) is an effective protective strategy against myocardial ischaemia-reperfusion (I/R) injury, but the precise mechanisms are far from clear. To understand the overall effects of IHH on the myocardial proteins during I/R, we analysed functional performance and the protein expression profile in isolated hearts from normoxic rats and from rats adapted to IHH (5000?m, 4?h?day(-1), 4?weeks) following I/R injury (30?min/45?min). Intermittent hypobaric hypoxia significantly improved the postischaemic recovery of left ventricular function compared with the recovery in time-matched normoxic control hearts. Two-dimensional electrophoresis with matrix-assisted laser desorption/ionization and time-of-flight mass spectrometric analysis was then used to assess protein alterations in left ventricles from normoxic and IHH groups, with or without I/R. The expressions of 16 proteins changed by over fivefold; nine of these proteins are involved in energy metabolism. Immunoblot and real-time PCR analysis confirmed the IHH-increased expressions of the ATP synthase subunit?β, mitochondrial aldehyde dehydrogenase and heat shock protein?27 in left ventricles. Furthermore, IHH significantly attenuated the reduction of myocardial ATP content, mitochondrial ATP synthase activity, membrane potential and respiratory control ratios due to I/R. In addition, inhibition of mitochondrial ATP synthase by oligomycin (1?μmol?l(-1)) abolished the IHH-induced improvements in three parameters: postischaemic recovery of left ventricular function, mitochondrial membrane potential and respiratory control ratios. These results suggest that an improvement in mitochondrial energy metabolism makes an important contribution to the cardioprotection afforded by IHH against postischaemic myocardial dysfunction.     

Regulation of iron metabolism and its involvement in diseases

Iron is an essential nutrient virtually almost all organisms including human, but at the same time, it is toxic because its high reactivity to molecular oxygen generates free radicals. Therefore, iron metabolism is tightly regulated. Recently, knowledge of roles that iron plays in our body as well as regulatory mechanism of iron metabolism in human body has been drastically expanded. Here I describe recent advance in our understanding on the regulation of iron metabolism and discuss its relationship to various diseases.     

The role of sialic acid as a modulator of the anti-inflammatory activity of IgG

Immunoglobulin G (IgG) molecules can have two completely opposing activities. They can be very potent pro-inflammatory mediators on the one hand, directing the effector functions of the innate immune system towards infected cells, tumor cells or healthy tissues in the case of autoimmune diseases. On the other hand, a mixture of IgG molecules purified from the blood of ten thousands of healthy donors is used as an anti-inflammatory treatment for many autoimmune diseases since several decades. It has become evident only recently that certain residues in the sugar moiety attached to the IgG constant fragment can dramatically alter the pro- and anti-inflammatory activities of IgG. This review will focus on sialic acid residues as a modulator of the anti-inflammatory activity and provide an overview of situations where serum IgG glycosylation and sialylation is altered and which molecular and cellular pathways may be involved in this immunomodulatory pathway.     

Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia

Mitochondrial ferritin (FtMt) is a nuclear-encoded iron-sequesteringprotein that specifically localizes in mitochondria. In miceit is highly expressed in cells characterized by high-energyconsumption, while is undetectable in iron storage tissues likeliver and spleen. FtMt expression in mammalian cells was shownto cause a shift of iron from cytosol to mitochondria, and inyeast it rescued the defects associated with frataxin deficiency.To study the role of FtMt in oxidative damage, we analyzed theeffect of its expression in HeLa cells after incubation withH₂O₂ and Antimycin A, and after a long-term growth in glucose-freemedia that enhances mitochondrial respiratory activity. FtMtreduced the level of reactive oxygen species (ROS), increasedthe level of adenosine 5'triphosphate and the activity of mitochondrialFe-S enzymes, and had a positive effect on cell viability. Furthermore,FtMt expression reduces the size of cytosolic and mitochondriallabile iron pools. In cells grown in glucose-free media, FtMtlevel was reduced owing to faster degradation rate, howeverit still protected the activity of mitochondrial Fe-S enzymeswithout affecting the cytosolic iron status. In addition, FtMtexpression in fibroblasts from Friedreich ataxia (FRDA) patientsprevented the formation of ROS and partially rescued the impairedactivity of mitochondrial Fe-S enzymes, caused by frataxin deficiency.These results indicate that the primary function of FtMt involvesthe control of ROS formation through the regulation of mitochondrialiron availability. They are consistent with the expression patternof FtMt observed in mouse tissues, suggesting a FtMt protectiverole in cells characterized by defective iron homeostasis andrespiration, such as in FRDA.     

The importance of TSLP in allergic disease and its role as a potential therapeutic target

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine similar to IL- 7, whose gene is located on chromosome 5q22.1 and it exerts its biological function through the TSLP-Receptor (TSLP-R). TSLP is expressed primarily by epithelial cells at barrier surfaces such as the skin, gut and lung in response to danger signals. Since it was cloned in 1994, there has been accumulating evidence that TSLP is crucial for the maturation of antigen presenting cells and hematopoietic cells. TSLP genetic variants and its dysregulated expression have been linked to atopic diseases such as atopic dermatitis, asthma, allergic rhinitis and eosinophilic esophagitis.     

Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease

Aging is associated with impaired mitochondrial function caused by accumulation of oxygen free radical-induced mitochondrial (Mt) DNA mutations. One prevailing theory is that age-associated diseases, including Alzheimer's disease (AD), may be precipitated, propagated, or caused by impaired mitochondrial function. To investigate the role of MtDNA relative to genomic (Gn) DNA damage in AD, temporal lobe samples from postmortem AD (n = 37) and control (n = 25) brains were analyzed for MtDNA and GnDNA fragmentation, mitochondrial protein and cytochrome oxidase expression, MitoTracker Green fluorescence (to assess mitochondrial mass/abundance), and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) immunoreactivity. Brains with AD had more extensive nicking and fragmentation of both MtDNA and GnDNA as demonstrated by agarose gel electrophoresis, end-labeling, and the in situ terminal deoxynucleotide transferase end-labeling (TUNEL) assay, and only the brains with AD had detectable 8-OHdG immunoreactivity in cortical neurons. Increased MtDNA damage in AD was associated with reduced MtDNA content, as demonstrated by semiquantitative PCR analysis and reduced levels of Mt protein and cytochrome oxidase expression by Western blot analysis or immunohistochemical staining with image analysis. The finding of reduced MitoTracker Green fluorescence in AD brains provided additional evidence that reduced Mt mass/abundance occurs with AD neurodegeneration. The presence of increased MtDNA and GnDNA damage in AD suggest dual cell death cascades in AD. Impaired mitochondrial function caused by MtDNA damage may render brain cells in AD more susceptible to oxidative injury and thereby provide a mechanism by which systemic or environmental factors could influence the course of disease.     

乳铁蛋白和脑铁代谢参与阿尔茨海默病

阿尔茨海默病(AD)是一种以脑内β-淀粉样蛋白(Aβ)逐渐沉积形成老年斑和tau蛋白过度磷酸化形成神经原纤维缠结为主要病理特征的神经退行性疾病。脑铁代谢紊乱促进阿尔茨海默病的发病进程,铁代谢异常能够促进AD脑内Aβ的沉积、tau蛋白过度磷酸化以及氧化应激反应等神经病理过程;而金属离子螯合剂如去铁敏等,可通过调节脑内铁离子代谢平衡,阻止Aβ的产生、tau蛋白磷酸化并改善学习记忆能力。乳铁蛋白(lactoferrin,LF)是一种具有铁螯合和抗炎作用的糖蛋白,在AD患者和转基因小鼠大脑Aβ斑块和神经原纤维缠结内均有明显表达,提示LF可能具有抑制AD脑内神经病理特征的产生的作用。因此,LF可能成为防治AD的候选药物之一。     

Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism

Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.