Role of mitochondria in liver metabolic health and diseases

International audienceThe liver is a major organ that coordinates the metabolic flexibility of the whole body, which is characterized by the ability to adapt dynamically in response to fluctuations in energy needs and supplies. In this context, hepatocyte mitochondria are key partners in fine-tuning metabolic flexibility. Here we review the metabolic and signalling pathways carried by mitochondria in the liver, the major pathways that regulate mitochondrial function and how they function in health and metabolic disorders associated to obesity, i.e. insulin resistance, non-alcoholic steatosis and steatohepatitis and hepatocellular carcinoma. Finally, strategies targeting mitochondria to counteract liver disorders are discussed

Metabolic signature of follicular fluid in infertility-related diseases: a narrative review

International audienceMetabolomics offers new methods to identify biomarkers for oocyte and embryo quality, and for a better understanding of the physiopathology of infertility. This review investigated the latest findings regarding metabolome-derived biomarkers in follicular fluid of women with the most common types of infertility, and the potential impact on reproductive medicine outcomes. PubMed was searched for publications on metabolomics and human follicular fluid, and key biomarkers, kinetics and relationships with infertility diseases were identified. A reduced concentration of glucose and increased concentrations of lactate and pyruvate were found in follicular fluid of patients with endometriosis and diminished ovarian reserve, and the opposite was found in patients with polycystic ovary syndrome. These signatures may lead to the hypothesis of changed metabolite concentrations in patients with endometriosis and diminished ovarian reserve, and a metabolic pathway alteration with decreased aerobic glycolysis in patients with polycystic ovary syndrome. However, the pattern found in patients with endometriosis and low responders may also be expected in follicular fluid of fertile women. Larger studies are needed to confirm the results. An international database may help to highlight follicular fluid biomarkers in order to improve the selection of cryopreserved oocytes, and to enrich culture medium to restore normal metabolism and improve reproductive treatment outcomes

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs

Differential effect of glucose on ER-mitochondria Ca(2+) exchange participates to insulin secretion and to glucotoxicity-mediated dysfunction of beta cells

Glucotoxicity-induced beta cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in beta cells is still largely unknown and their implication in glucotoxicity-associated beta cell dysfunction remains to be defined. Here, we report that acute glucose stimulation stimulated ER-mitochondria interactions and calcium (Ca(2+)) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS, and concomitantly reduced ER Ca(2+) store, increased basal mitochondrial Ca(2+) and reduced ATP-stimulated ER-mitochondria Ca(2+) exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca(2+) signaling are associated with ER stress, altered mitochondrial respiration and mitochondria fragmentation, and these organelle stresses may participate to increased organelle tethering, as a protective mechanism. Lastly, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca(2+) exchange, induced mitochondrial fission and altered GSIS. Therefore, dynamic organelle coupling participates to GSIS in beta cells and over-time disruption of organelle Ca(2+) exchange might be a novel mechanism contributing to glucotoxicity-induced beta cell dysfunction

Dietary obesity in mice is associated with lipid deposition and metabolic shifts in the lungs sharing features with the liver

International audienceObesity is associated with both chronic and acute respiratory illnesses, such as asthma, chronic obstructive pulmonary disease (COPD) or increased susceptibility to infectious diseases. Anatomical but also systemic and local metabolic alterations are proposed contributors to the pathophysiology of lung diseases in the context of obesity. To bring perspective to this discussion, we used NMR to compare the obesity-associated metabolomic profiles of the lung with those of the liver, heart, skeletal muscles, kidneys, brain and serum from male C57Bl/6J mice fed with a high-fat and high-sucrose (HFHSD) diet vs. standard (SD) chow for 14 weeks. Our results showed that the lung was the second most affected organ after the liver, and that the two organs shared reduced one-carbon (1C) metabolism and increased lipid accumulation. Altered 1C metabolism was found in all organs and in the serum, but serine levels were increased only in the lung of HFHSD compared to SD. Lastly, tricarboxylic acid (TCA)-derived metabolites were specifically and oppositely regulated in the serum and kidneys but not in other organs. Collectively, our data highlighted that HFHSD induced specific metabolic changes in all organs, the lung being the second most affected organ, the main alterations affecting metabolite concentrations of the 1C pathway and, to a minor extend, TCA. The absolute metabolite quantification performed in this study reveals some metabolic specificities affecting both the liver and the lung, that may reveal common metabolic determinants to the ongoing pathological process

Dietary obesity in mice is associated with lipid deposition and metabolic shifts in the lungs sharing features with the liver

AbstractObesity is associated with both chronic and acute respiratory illnesses, such as asthma, chronic obstructive pulmonary disease (COPD) or increased susceptibility to infectious diseases. Anatomical but also systemic and local metabolic alterations are proposed contributors to the pathophysiology of lung diseases in the context of obesity. To bring perspective to this discussion, we used NMR to compare the obesity-associated metabolomic profiles of the lung with those of the liver, heart, skeletal muscles, kidneys, brain and serum from male C57Bl/6J mice fed with a high-fat and high-sucrose (HFHSD) diet vs. standard (SD) chow for 14 weeks. Our results showed that the lung was the second most affected organ after the liver, and that the two organs shared reduced one-carbon (1C) metabolism and increased lipid accumulation. Altered 1C metabolism was found in all organs and in the serum, but serine levels were increased only in the lung of HFHSD compared to SD. Lastly, tricarboxylic acid (TCA)-derived metabolites were specifically and oppositely regulated in the serum and kidneys but not in other organs. Collectively, our data highlighted that HFHSD induced specific metabolic changes in all organs, the lung being the second most affected organ, the main alterations affecting metabolite concentrations of the 1C pathway and, to a minor extend, TCA. The absolute metabolite quantification performed in this study reveals some metabolic specificities affecting both the liver and the lung, that may reveal common metabolic determinants to the ongoing pathological process.</jats:p