Iron Metabolism in the Disorders of Heme Biosynthesis

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncon- trolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordina- tion complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen- binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron- dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different por- phyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mito- chondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay be- tween iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis

Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.

Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.GM’s laboratory is supported by grants from Armenise-Harvard Foundation and Telethon Foundation (TCP13013). The Cambridge Stem Cell Institute receives core funding from the Wellcome Trust and Medical Research Council. GM was supported by a Human Frontier Science Program Fellowship. AS is a Medical Research Professor.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.15252/embj.20159262

Mast Cell: An Emerging Partner in Immune Interaction

Mast cells (MCs) are currently recognized as effector cells in many settings of the immune response, including host defense, immune regulation, allergy, chronic inflammation, and autoimmune diseases. MC pleiotropic functions reflect their ability to secrete a wide spectrum of preformed or newly synthesized biologically active products with pro-inflammatory, anti-inflammatory and/or immunosuppressive properties, in response to multiple signals. Moreover, the modulation of MC effector phenotypes relies on the interaction of a wide variety of membrane molecules involved in cell–cell or cell-extracellular-matrix interaction. The delivery of co-stimulatory signals allows MC to specifically communicate with immune cells belonging to both innate and acquired immunity, as well as with non-immune tissue-specific cell types. This article reviews and discusses the evidence that MC membrane-expressed molecules play a central role in regulating MC priming and activation and in the modulation of innate and adaptive immune response not only against host injury, but also in peripheral tolerance and tumor-surveillance or -escape. The complex expression of MC surface molecules may be regarded as a measure of connectivity, with altered patterns of cell–cell interaction representing functionally distinct MC states. We will focalize our attention on roles and functions of recently discovered molecules involved in the cross-talk of MCs with other immune partners

Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca2+-activated K+ channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures

Reduction of circulating sphingosine 1-phosphate worsens mdx soleus muscle dystrophic phenotype

What is the central question of the study? What are the consequences of reducing circulating Sphingosine-1-phosphate (S1P) on muscle physiology in the murine model of Duchenne muscular dystrophy (DMD)? What is the main result and its importance? Reducing circulating S1P level in mdx mice aggravates the dystrophic phenotype, as seen by an increase in fiber atrophy, fibrosis, and loss of specific force, suggesting that S1P signaling is a potential therapeutic target in DMD. While further studies are needed, plasma S1P levels have the intriguing possibility of being used as a biomarker for disease severity, an important issue in DMD

Role of sphingosylphosphorylcholine on skeletal muscle denervation and regeneration

Present work is aimed at studying the role of sphingosylphosphorylcholine (SPC), a natural bioactive sphingomyelin derivative, on denervation and regeneration of skeletal muscle. SPC is known to participate in growth, proliferation and survival of various cell systems. The experiments were performed in adult rats. SPC was continuously released by a mini-osmotic pumps connected by a catheter to control, denervated or regenerating (after bupivacaine injection) soleus muscles. Supplementation of SPC to adult muscles, produced significant atrophy of fibres and light changes to fibre type composition. In contrast, SPC did not influence denervation atrophy. During regeneration, SPC produced alterations on fibre dimensions and on myosin expression. In conclusion, it appears that SPC exerts distinctive actions depending on definite condition of skeletal muscl

Effects of sphingomyelin derivatives on innervated and denervated rat soleus muscle

Present work is aimed at studying the effects of natural bioactive sphingomyelin derivatives, on normal and denervated slow-twitch skeletal muscle. The effects on fibre cross sectional area and myosin heavy chains composition of sphingosine (SPH), sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) were studied. Denervation was bilaterally performed cutting the sciatic nerve at the level of trochanter in adult rats. A group of animals was used as controls. Sphingolipids were continuously released by a mini-osmotic pumps implanted subcutaneously in the scapular region and connected by a catheter to the left (control or denervated) soleus muscles. Supplementation of SPC to adult control soleus muscle, produced significant atrophy of fibres and small changes to fibre type composition. No significant effects of SPH and S1P were found. In contrast, SPH and, to a smaller extent, S1P reduced the atrophy and the slow-to-fast transformation produced by 7-14 days of denervation. Preliminary results indicate that these sphingolipids may exert their action by reducing the overall muscle apoptosis and by activating satellite cells