Regulation Of Energetic Metabolism Research Articles

Role of mitochondria-associated endoplasmic reticulum membranes in insulin sensitivity, energy metabolism, and contraction of skeletal muscle.

Skeletal muscle has a critical role in the regulation of the energy balance of the organism, particularly as the principal tissue responsible for insulin-stimulated glucose disposal and as the major site of peripheral insulin resistance (IR), which has been related to accumulation of lipid intermediates, reduced oxidative capacity of mitochondria and endoplasmic reticulum (ER) stress. These organelles form contact sites, known as mitochondria-associated ER membranes (MAMs). This interconnection seems to be involved in various cellular processes, including Ca2+ transport and energy metabolism; therefore, MAMs could play an important role in maintaining cellular homeostasis. Evidence suggests that alterations in MAMs may contribute to IR. However, the evidence does not refer to a specific subcellular location, which is of interest due to the fact that skeletal muscle is constituted by oxidative and glycolytic fibers as well as different mitochondrial populations that appear to respond differently to stimuli and pathological conditions. In this review, we show the available evidence of possible differential responses in the formation of MAMs in skeletal muscle as well as its role in insulin signaling and the beneficial effect it could have in the regulation of energetic metabolism and muscular contraction.

Urbanization drives adaptive evolution in a Neotropical bird.

Urbanization has dramatic impacts on natural habitats and such changes may potentially drive local adaptation of urban populations. Behavioral change has been specifically shown to facilitate the fast adaptation of birds to changing environments, but few studies have investigated the genetic mechanisms of this process. Such investigations could provide insights into questions about both evolutionary theory and management of urban populations. In this study, we investigated whether local adaptation has occurred in urban populations of a Neotropical bird species, Coereba flaveola, specifically addressing whether observed behavioral adaptations are correlated to genetic signatures of natural selection. To answer this question, we sampled 24 individuals in urban and rural environments, and searched for selected loci through a genome-scan approach based on RADseq genomic data, generated and assembled using a reference genome for the species. We recovered 46 loci as putative selection outliers, and 30 of them were identified as associated with biological processes possibly related to urban adaptation, such as the regulation of energetic metabolism, regulation of genetic expression, and changes in the immunological system. Moreover, genes involved in the development of the nervous system showed signatures of selection, suggesting a link between behavioral and genetic adaptations. Our findings, in conjunction with similar results in previous studies, support the idea that cities provide a similar selective pressure on urban populations and that behavioral plasticity may be enhanced through genetic changes in urban populations.

Catalogue of stage-specific transcripts in Ixodes ricinus and their potential functions during the tick life-cycle

BackgroundThe castor bean tick Ixodes ricinus is an important vector of several clinically important diseases, whose prevalence increases with accelerating global climate changes. Characterization of a tick life-cycle is thus of great importance. However, researchers mainly focus on specific organs of fed life stages, while early development of this tick species is largely neglected.MethodsIn an attempt to better understand the life-cycle of this widespread arthropod parasite, we sequenced the transcriptomes of four life stages (egg, larva, nymph and adult female), including unfed and partially blood-fed individuals. To enable a more reliable identification of transcripts and their comparison in all five transcriptome libraries, we validated an improved-fit set of five I. ricinus-specific reference genes for internal standard normalization of our transcriptomes. Then, we mapped biological functions to transcripts identified in different life stages (clusters) to elucidate life stage-specific processes. Finally, we drew conclusions from the functional enrichment of these clusters specifically assigned to each transcriptome, also in the context of recently published transcriptomic studies in ticks.ResultsWe found that reproduction-related transcripts are present in both fed nymphs and fed females, underlining the poorly documented importance of ovaries as moulting regulators in ticks. Additionally, we identified transposase transcripts in tick eggs suggesting elevated transposition during embryogenesis, co-activated with factors driving developmental regulation of gene expression. Our findings also highlight the importance of the regulation of energetic metabolism in tick eggs during embryonic development and glutamate metabolism in nymphs.ConclusionsOur study presents novel insights into stage-specific transcriptomes of I. ricinus and extends the current knowledge of this medically important pathogen, especially in the early phases of its development.

First person – Rafael José Argüello

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Rafael José Argüello is the first author on ‘SunRiSE – measuring translation elongation at single-cell resolution by means of flow cytometry’, published in Journal of Cell Science. Rafael is a researcher in the lab of Philippe Pierre at Centre d'Immunologie de Marseille-Luminy, Marseille, France, investigating tRNAs and translation, and the regulation of energetic metabolism in the context of infection and cancer.

TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor.

Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.

PGC-1α-Derived Peptide Influences Energy in Normal Human Dermal Fibroblasts

Mitochondrial energy metabolism declines during aging. PGC-1α is a transcription coactivator that plays a key role in the regulation of energetic metabolism and mitochondrial biogenesis in the cells. The aim of this study was to compare the PPARGC1A gene expression level in normal human dermal fibroblasts (NHDF) derived from young and old donors. A PGC-1α-derived peptide was then synthetized and its ability to affect the PPARGC1A gene expression and mitochondrial function was tested. We assessed changes in PPARGC1A gene expression using quantitative RT-PCR. The effect of the PGC-1α-derived peptide on energy production was determined using an ATP bioluminescent assay kit. We also studied changes in mitochondrial membrane potential using JC-1 fluorescent dye and the level of reactive oxygen species (ROS) using DCFH-DA dye in NHDF cells after UVA/B irradiation alone and in combination with a peptide treatment. The PPARGC1A gene expression decreased in an aged human dermal fibroblast. The PGC-1α-derived peptide was synthetized and increased the PPARGC1A gene expression and ATP levels in cells. Furthermore, the mitochondrial membrane potential in UVA/B irradiated cells treated with the tested PGC-1α-derived peptide was increased compared to irradiated controls. Moreover, the ROS levels in UVA/B irradiated cells treated with the PGC-1α-derived peptide decreased. On the basis of our results, PGC-1α emerges as an interesting target to combat decreasing energetic metabolism in aging skin cells. Indeed, the PGC-1α-derived peptide increasing the PPARGC1A gene expression improved the mitochondrial function and increased energy production in the cells.

The regulation effect of AMPK in immune related diseases.

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation. Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.

New insights into circulating FABP4: Interaction with cytokeratin 1 on endothelial cell membranes

Fatty acid-binding protein 4 (FABP4) is an adipose tissue-secreted adipokine that is involved in the regulation of energetic metabolism and inflammation. Increased levels of circulating FABP4 have been detected in individuals with cardiovascular risk factors. Recent studies have demonstrated that FABP4 has a direct effect on peripheral tissues, specifically promoting vascular dysfunction; however, its mechanism of action is unknown. The objective of this work was to assess the specific interactions between exogenous FABP4 and the plasma membranes of endothelial cells. Immunofluorescence assays showed that exogenous FABP4 localized along the plasma membranes of human umbilical vein endothelial cells (HUVECs), interacting specifically with plasma membrane proteins. Anti-FABP4 immunoblotting revealed two covalent protein complexes containing FABP4 and its putative receptor; these complexes were approximately 108kDa and 77kDa in size. Proteomics and mass spectrometry experiments revealed that cytokeratin 1 (CK1) was the FABP4-binding protein. An anti-CK1 immunoblot confirmed the presence of CK1. FABP4-CK1 complexes were also detected in HAECs, HCASMCs, HepG2 cells and THP-1 cells. Pharmacological FABP4 inhibition by BMS309403 results in a slight decrease in the formation of these complexes, indicating that fatty acids may play a role in FABP4 functionality. In addition, we demonstrated that exogenous FABP4 crosses the plasma membrane to enter the cytoplasm and nucleus in HUVECs. These findings indicate that exogenous FABP4 interacts with plasma membrane proteins, specifically CK1. These data contribute to our current knowledge regarding the mechanism of action of circulating FABP4.

The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis.

In the recent years, we have provided evidence that Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) is a key stress protein with antioxidant-associated tumor suppressive function. The TP53INP1 gene, which is highly conserved in mammals, is over-expressed during stress responses including inflammation. This gene encodes two protein isoforms with nuclear or cytoplasmic subcellular localization depending on the context. TP53INP1 contributes to stress responses, thus preventing stress-induced dysfunctions leading to pathologies such as cancer. Two major mechanisms by which TP53INP1 functions have been unveiled. First, in the nucleus, TP53INP1 was shown to regulate the transcriptional activity of p53 and p73 by direct interaction, and to mediate the antioxidant activity of p53. Second, independently of p53, TP53INP1 contributes to autophagy and more particularly mitophagy through direct interaction with molecular actors of autophagy. TP53INP1 is thus required for the homeostasis of the mitochondrial compartment, and is therefore involved in the regulation of energetic metabolism. Finally, the antioxidant function of TP53INP1 stems from the control of mitochondrial reactive oxygen species production. In conclusion, TP53INP1 is a multifaceted protein endowed with multiple functions, including metabolic regulation, as is its main functional partner p53.

Differential protein profile in sexed bovine semen: shotgun proteomics investigation

The preparation of sexed semen is based on the differential DNA content between the X and Y chromosome bearing sperm cells determined by fluorescence-activated cell sorting. In spite of its intrinsic limitations this represents the only effective method. However, the employment of sexed sperm for breeding food producing animals on a large scale requires additional knowledge in the protein repertoire for the development of improved methods to differentiate X and Y sperm cells maintaining high vitality. In order to address this issue, we performed a comparative shotgun proteomic investigation by nUPLC-MS/MS to characterize sexed bovine semen. The protein profiles of these two types of sperm cells have shown differential expression of proteins that may be directly associated with the main components of cytoskeletal structures of flagellum, as the axoneme, outer dense fibers and fibrous sheath, as well as glycolytic enzymes and calmodulin, involved in the energetic metabolism regulation. Overall these results may provide a base to a better comprehension of the biological features of sperm cells and may be useful to the development of alternative methods of separation.

Resveratrol Induces a Mitochondrial Complex I-dependent Increase in NADH Oxidation Responsible for Sirtuin Activation in Liver Cells

Resveratrol (RSV) has been shown to be involved in the regulation of energetic metabolism, generating increasing interest in therapeutic use. SIRT1 has been described as the main target of RSV. However, recent reports have challenged the hypothesis of its direct activation by RSV, and the signaling pathways remain elusive. Here, the effects of RSV on mitochondrial metabolism are detailed both in vivo and in vitro using murine and cellular models and isolated enzymes. We demonstrate that low RSV doses (1-5 μM) directly stimulate NADH dehydrogenases and, more specifically, mitochondrial complex I activity (EC50 ∼1 μM). In HepG2 cells, this complex I activation increases the mitochondrial NAD(+)/NADH ratio. This higher NAD(+) level initiates a SIRT3-dependent increase in the mitochondrial substrate supply pathways (i.e. the tricarboxylic acid cycle and fatty acid oxidation). This effect is also seen in liver mitochondria of RSV-fed animals (50 mg/kg/day). We conclude that the increase in NADH oxidation by complex I is a crucial event for SIRT3 activation by RSV. Our results open up new perspectives in the understanding of the RSV signaling pathway and highlight the critical importance of RSV doses used for future clinical trials.

PLACEBO-DRIVEN CLINICAL TRIALS OF TRANSFER POINT GLUCAN #300 IN CHILDREN WITH CHRONIC RESPIRATORY PROBLEMS: III. CLINICAL FINDINGS

The role of glucan in stimulation of immune reactio ns has been studied for decades. In this report we focused on the effects of orally administered gluca n in children with chronic respiratory problems. We measured the physical endurance using a 6MWT test and the levels of eNO in 50 children aged 8-12 years and evaluated the effects of 100 mg/d oral dose of glucan. We found significant improvements in physical indurance and exhaled nitric oxide in glucan-treate d children. In addition, strong improvements in gen eral conditions were found. Short-term oral application of natural immunomodulator β-glucan enhancers the overall health and regulation of energetic metaboli sm in children with chronic respiratory problems.

Emerging role of neuregulin as a modulator of muscle metabolism

Neuregulin was described initially as a neurotrophic factor involved in the formation of the neuromuscular junction in skeletal muscle. However, in recent years, neuregulin has been reported to be a myokine that exerts relevant effects on myogenesis and the regulation of muscle metabolism. In this new context, the rapid and chronic metabolic effects of neuregulin appear to be related to muscle contraction. Indeed, the effects of neuregulin resemble those of exercise, which are accompanied by an improvement in insulin sensitivity. In this review, we challenge the classical role assigned to neuregulin in muscle and propound the emerging concept of its involvement in the regulation of energetic metabolism and insulin responsiveness.

Expression patterns of AMP-deaminase isozymes in human hepatocellular carcinoma (HCC).

AMP-deaminase (EC 3.5.4.6) is an enzyme of nucleotide breakdown involved in regulation of energetic metabolism in mammalian cells. The enzyme is coded by a family of three independent genes (AMPD1, AMPD2 and AMPD3), synthesizing three different isozymes. In mammalian liver, the reaction catalyzed by AMP-deaminase constitutes a rate-limiting step in adenine nucleotide catabolism. In neoplastic liver, adenine nucleotide catabolism is a subject of many modifications, which influence the expression of genes synthesizing enzymes regulating this pathway. The experimental studies presented here illustrate the expression of AMPD genes in human liver neoplasm tumor (HCC, hepatocellular carcinoma). RT-PCR and Western blotting methods were used for determining of the goal mentioned above. Expression level of AMPD gene family in the tumorous fragment (HCC tumor) of neoplastic liver did not differ substantially from that found in the nontumorous (cirrhotic) fragment of the organ. In this case the expression of AMPD2 gene was prevailing. AMPD2 was the main isoform of AMP-deaminase identified in two liver fragments compared. This is a first report evidencing the pattern of AMPD genes expression in neoplastic human liver.

Organ preservation during experimental liver transplantation.

The liver is a key-organ in the regulation of energetic metabolism; it supplies lipids, nucleotides and vitamins to the whole organism. Almost all these synthesis are highly dependent from oxygen availability which may lead to decreased liver functions, cellular suffering, death and inflammation. A better understanding of tissue energy metabolism and antioxidant status is of great interest in the field of liver preservation for transplantation. The lack of oxygen and the reperfusion after periods of hypoxia during transplantation, leads to ATP breakdown and depletion of the naturally occurring defences. Nucleotides degrade rapidly during cold storage, forming end-products which flow freely through the plasma membrane. Depletion of mitochondrial superoxide-dismutase (SOD) and glutathione makes the liver vulnerable to oxygen free radicals1. It is well known that reactive oxygen species resulting from the ischemia-reperfusion sequence are mediators of cellular damage2. A burst of free radical production is thought to occur when the organ undergoes global ischemia, overwhelming the scavenging capacity of the hepathocytes and preventing restoration of the normal energy balance. Nucleotide and glutathione determinations are widely accepted tools in the evaluation of cellular energy and antioxidant status3.

Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum

Several electrophysiological studies have addressed the interaction between glutamate and dopamine within the striatum. Although the results obtained from these studies were often conflicting, more recently the characterization of new forms of synaptic plasticity in the basal ganglia provided a possible integrative explanation of the different electrophysiological data regarding the interaction between these transmitters. In this review we will try to summarize and discuss the available data concerning the possible impact of the functional role of D1 and D2 receptor activation on the modulation of the glutamatergic corticostriatal pathway. Moreover, we will also describe the function of the striatum in the integration of glutamatergic and dopaminergic inputs to produce long-term changes of synaptic efficacy (long-term depression, long-term potentiation). Finally, we will consider the implication of the interaction between dopamine and glutamate in the regulation of energetic metabolism whose failure is responsible for neuronal death.