Selection of major scientific publications of CarMeN laboratory

Glucose is a new regulator of mitochondria-associated endoplasmic reticulum membranes (MAM) dynamics in the liver.

Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dynamics and function and in hepatic insulin action. In this study, we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver. Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity. Both in vitro and in vivo, glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A (PP-PP2A) pathway, induced mitochondria fission, and impaired respiration. Blocking MAM reduction counteracted glucose-induced mitochondrial alterations. Furthermore, disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function. This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice, both characterized by chronic disruption of MAM integrity, mitochondrial fission, and altered mitochondrial respiration. These data indicate that MAM contribute to the hepatic glucose-sensing system, allowing regulation of mitochondria dynamics and function during nutritional transition. Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance

 

Theurey P et al. J Mol Cell Biol. 2016, 8:129-43. PubMed

Exosome-like vesicles released from insulin-resistant muscles modulate gene expression and proliferation of recipient beta cells.

The crosstalk between skeletal muscle (SkM) and beta cells plays a role in diabetes aetiology. In this study, we have investigated whether SkM-released exosome-like vesicles (ELVs) can be taken up by pancreatic beta cells and can deliver functional cargoes. Mice were fed for 16 weeks with standard chow diet (SCD) or with standard diet enriched with 20% palmitate (HPD) and ELVs were purified from quadriceps muscle. Fluorescent ELVs from HPD or SCD quadriceps were injected i.v. or intramuscularly (i.m.) into mice to determine their biodistributions. We found that muscle ELVs were taken up by pancreas, 24 h post-injection. In vitro, both SD-ELVs and HPD-ELVs transferred proteins and miRNAs to MIN6B1 cells and modulated gene expressions, whereas only HPD-ELVs induced proliferation of MIN6B1 cells and isolated islets. Bioinformatic analyses suggested that transferred HPD-ELV miRNAs may participate in these effects. To validate this, we demonstrated that miR-16, which is overexpressed in HPD-ELVs, was transferred to MIN6B1 cells and regulated Ptch1, involved in pancreas development. Our data suggest that muscle ELVs might have an endocrine effect and could participate in adaptations in beta cell mass during insulin resistance.

 

Jalabert A et al.  Diabetologia. 2016, 59:1049-58. PubMed

Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) are functional domains between both organelles involved in Ca2+ exchange, through the voltage-dependent anion channel (VDAC)-1/glucose-regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (IP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca2+ homeostasis are associated with altered insulin signaling, the implication of MAM dysfunctions in insulin resistance is unknown. Here we validated an approach based on in situ proximity ligation assay to detect and quantify VDAC1/IP3R1 and Grp75/IP3R1 interactions at the MAM interface. We demonstrated that MAM integrity is required for insulin signaling and that induction of MAM prevented palmitate-induced alterations of insulin signaling in HuH7 cells. Disruption of MAM integrity by genetic or pharmacological inhibition of the mitochondrial MAM protein, cyclophilin D (CypD), altered insulin signaling in mouse and human primary hepatocytes and treatment of CypD knockout mice with metformin improved both insulin sensitivity and MAM integrity. Furthermore, ER-mitochondria interactions are altered in liver of both ob/ob and diet-induced insulin-resistant mice and improved by rosiglitazone treatment in the latter. Finally, increasing organelle contacts by overexpressing CypD enhanced insulin action in primary hepatocytes of diabetic mice. Collectively, our data reveal a new role of MAM integrity in hepatic insulin action and resistance, providing a novel target for the modulation of insulin action.

Tubbs E. et al Diabetes. 2014, 63:3279-94 (Team 3) Pubmed

The new antidiabetic drug Imeglimin normalizes glucose tolerance and insulin sensitivity in mice via improvement of mitochondrial function in liver.

Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.

 

Vial et al. Diabetes. 2015, 64:2254-64 (teams 1 and 3) PubMed

Ozone Exposure Triggers Insulin Resistance Through Muscle c-Jun N-terminal Kinases (JNKs) Activation

A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 ppm), we demonstrated that exposition of rats to ozone induced whole body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, JNK activation and disruption of insulin signaling in skeletal muscle. Broncho-alveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pre-treatments with the chemical chaperone 4-phenyl butyric acid, the JNK inhibitor SP600125 or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress and JNK activation to impair insulin signaling in muscle. This study is the first report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases.

Vella RE et al Diabetes. 2015 64:1011-24 (Team 1) Pubmed

Exosomes released from cells can transfer both functional proteins and RNAs between cells

In this study we tested the hypothesis that muscle cells might transmit specific signals during lipid-induced insulin resistance through the exosomal route.Exosomes were collected from quadriceps muscles of C57Bl/6 mice fed for 16 weeks with either a standard chow diet (SD) or an SD enriched with 20% palm oil (HP) and from C2C12 cells exposed to 0.5 mmol/l palmitate (EXO-Post Palm), oleate (EXO-Post Oleate) or BSA (EXO-Post BSA).HP-fed mice were obese and insulin resistant and had altered insulin-induced Akt phosphorylation in skeletal muscle (SkM). They also had reduced expression of Myod1 and Myog and increased levels of Ccnd1 mRNA, indicating that palm oil had a deep impact on SkM homeostasis in addition to insulin resistance. HP-fed mouse SkM secreted more exosomes than SD-fed mouse SkM. This was reproduced in-vitro using C2C12 cells pre-treated with palmitate, the most abundant saturated fatty acid of palm oil. Exosomes from HP-fed mice, EXO-Post Palm and EXO-Post Oleate induced myoblast proliferation and modified the expressions of genes involved in the cell cycle and muscle differentiation but did not alter insulin-induced Akt phosphorylation. Lipidomic analyses showed that exosomes from palmitate-treated cells were enriched in palmitate, indicating that exosomes likely transfer the deleterious effect of palm oil between muscle cells by transferring lipids. Muscle exosomes were incorporated into various tissues in vivo, including the pancreas and liver, suggesting that SkM could transfer specific signals through the exosomal route to key metabolic tissues. Exosomes act as ‘paracrine-like’ signals and modify muscle homeostasis during high-fat diets.

Aswad H et al Diabetologia 2014 57:2155-64 (Team 2) Pubmed

Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition

In most animal species, juvenile growth is marked by an exponential gain in body weight and size. Here we show that the microbiota of infant mice sustains both weight gain and longitudinal growth when mice are fed a standard laboratory mouse diet or a nutritionally depleted diet. We found that the intestinal microbiota interacts with the somatotropic hormone axis to drive systemic growth. Using monocolonized mouse models, we showed that selected lactobacilli promoted juvenile growth in a strain-dependent manner that recapitulated the microbiota’s effect on growth and the somatotropic axis. These findings show that the host’s microbiota supports juvenile growth. Moreover, we discovered that lactobacilli strains buffered the adverse effects of chronic undernutrition on the postnatal growth of germ-free mice.

 

Schwarzer M et al.  Science. 2016, 351:854-7. PubMed

Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion.

Circadian clocks are functional in all light-sensitive organisms, allowing an adaptation to the external world in anticipation of daily environmental changes. Here we aimed to characterize circadian rhythms in primary human skeletal myotubes and investigate their roles in myokine secretion. We established a system for long-term bioluminescence recording in differentiated human myotubes, employing lentivector gene delivery of the Bmal1-luciferase and Per2-luciferase core clock reporters. This bioluminescence reporter assays revealed that human skeletal myotubes, synchronized in vitro, exhibit a self-sustained circadian rhythm, which was further confirmed by endogenous core clock transcript expression. Moreover, we demonstrate that the basal secretion of IL-6, IL-8 and MCP-1 by synchronized skeletal myotubes has a circadian profile. Importantly, the secretion of IL-6 and several additional myokines was strongly downregulated upon siClock-mediated clock disruption. Our study provides for the first time evidence that primary human skeletal myotubes possess a high-amplitude cell-autonomous circadian clock, which plays an important role in the regulation of basal myokine secretion by skeletal myotubes.

 

Perrin L et al.  Mol Metab. 2015, 4:834-45. PubMed

Postprandial Endotoxemia Linked With Chylomicrons and Lipopolysaccharides Handling in Obese Versus Lean Men: A Lipid Dose-Effect Trial.

Postprandial endotoxemia is a metabolic risk factor, which has been shown to originate from the intestinal absorption of gut lipopolysaccharides (LPS) using nonphysiological high-fat tests. This study aimed to determine whether different realistic fat amounts can modulate postprandial dynamics and handling of LPS by varying postprandial lipidemia in humans of different body mass indices. In a randomized, controlled, cross-over study in nutrition research center, eight normal-weight (NW) and eight obese age-matched men, without diabetes nor dyslipidemia, ingested breakfasts containing 10 vs 40 g fat. Chylomicronemia increased in all subjects according to ingested fat amount (P < .01), but only obese had higher postprandial endotoxemia after 40 g (P < .05). Obese subject chylomicrons were more enriched with LPS compared with NW (PBMI < .01). We observed neither NF-κB translocation, nor variation of IL-6 expression in leukocytes. In both groups, fat amount did not modify postprandial response of plasma IL-6. However, the area under the curve (AUC) of IL-6 in obese was higher than in NW (P < .05) parallel to higher fasting LPS-binding protein (LBP; P < .05). This study demonstrates thus that postprandial endotoxemia is modulated by ingested fat amount in obese men.

 

Vors C et al. J Clin Endocrinol Metab. 2015, 100:3427-35. PubMed

Adipose Tissue-Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation.

Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNCs) is well established in obesity, the functional consequences of these interactions are less understood. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and 3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs-with a contribution of intracellular adhesion molecule-1-and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.

 

Eljaafari A  et al. Diabetes. 2015, 64:2477-88. PubMed

Regulation of energy metabolism and mitochondrial function in skeletal muscle during lipid overfeeding in healthy men.

The aim of this study was to evaluate the regulation of the fuel partitioning and energy metabolism in skeletal muscle during lipid overfeeding in healthy men. 39 healthy volunteers were overfed for 56 days with a high-fat diet (3180 kJ/d). Energy metabolism (indirect calorimetry) was characterized in the fasting state and during a test meal before and at the end of the diet. Skeletal muscle biopsies were taken at day 0 and day 56. Overfeeding increased body weight (+2.6 kg) and fat mass concomitantly with a shift in the use of substrates as energy fuel toward preferential oxidation of carbohydrates instead of lipids. Changes in lipid metabolic gene expression supported this observation, with a reduction in pyruvate dehydrogenase kinase 4 expression that could be the consequences of decreased NAD(+) concentration and reduced deacetylase activity of the sirtuins, as supported by hyperacetylation of PGC-1α after overfeeding. Interestingly, this reduction of the sirtuin PGC-1α pathway was associated with increased mitochondrial gene expression and higher respiration rate under these conditions. We concluded that adaptation to lipid overfeeding and regulation of fuel partitioning in human muscle appear to rely on a dissociation between the regulatory functions of the sirtuin-PGC-1α pathway on fatty acid oxidation and on mitochondrial regulation. This may facilitate lipid storage during a period of positive energy balance while maintaining mitochondrial functions and oxidative capacities.

Seyssel K et al., J Clin Endocrinol Metab. 2014 99:E1254-62. PubMed

An APOA5 3′ UTR Variant Associated with Plasma Triglycerides Triggers APOA5 Downregulation by Creating a Functional miR-485-5p Binding Site.

APOA5 is a major actor of triglyceride rich lipoproteins (TGRL) metabolism, activating lipoprotein lipase activity and regulating TGRL hepatic clearance. APOA5 haplotype 2 (APOA5*2) is strongly associated with plasma triglyceride level and modulates the occurrence of both moderate and severe hypertriglyceridemia, but his functionality remains unknown. Individuals with APOA5*2 display reduced APOA5 expression at the post-transcriptional level. APOA5 c.*158C>T (rs2266788), located in the 3′ UTR, belongs to APOA5 haplotype 2. We hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3′ UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p in the mutant APOA5 3′ UTR with the c. *158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3′ UTR luciferase reporter vector and a miR485-5p precursor, c. *158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.*158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 post-transcriptional downregulation mediated by miR-485-5p.

Caussy C et al, Am J Hum Genet. 2014 Jan 2;94(1):129-34 (Teams 2 and 4)Pubmed

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury.

Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia-reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. We questioned here whether GSK3β might have a role in the Ca(2+) transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP3Rs) Ca(2+) channeling complex in MAMs. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP3R phosphorylation, which leads to enhanced transfer of Ca(2+) from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP3R phosphorylation and SR/ER Ca(2+) release, which consequently diminished both cytosolic and mitochondrial Ca(2+) concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca(2+) leak from IP3R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca(2+) overload and subsequent cell death.

 

Gomez L et AL. Cell Death Differ. 2016 23:313-22. PubMed

Cyclosporine in acute ischemic stroke.

We examined whether IV administration of cyclosporine in combination with thrombolysis might reduce cerebral infarct size. Patients aged 18 to 85 years, presenting with an anterior-circulation stroke and eligible for thrombolytic therapy, were enrolled in this multicenter, single-blinded, controlled trial. Fifteen minutes after randomization, patients received either an IV bolus injection of 2.0 mg/kg cyclosporine (Sandimmune, Novartis) or placebo. The primary endpoint was infarct volume on MRI at 30 days. Secondary endpoints included infarct volume according to the site (proximal/distal) of arterial occlusion and recanalization after thrombolysis.

From October 2009 to July 2013, 127 patients were enrolled. The primary endpoint was assessed in 110 of 127 patients. The reduction of infarct volume in the cyclosporine compared with the control group was overall not significant (21.8 mL [interquartile range, IQR 5.1, 69.2 mL] vs 28.8 mL [IQR 7.7, 95.0 mL], respectively; p = 0.18). However, in patients with proximal occlusion and effective recanalization, infarct volume was significantly reduced in the cyclosporine compared with the control group (14.9 mL [IQR 1.3, 23.2 mL] vs 48.3 mL [IQR 34.5, 118.2 mL], respectively; p = 0.009).

Cyclosporine was generally not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral artery occlusion and efficient recanalization. This study provides Class I evidence that in patients with an acute anterior-circulation stroke, thrombolysis plus IV cyclosporine does not significantly decrease 30-day MRI infarct volume compared with thrombolysis alone.

 

Nighoghossian N et al. Neurology. 2015, 84:2216-23. PuBMed

Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year.

A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups.

We conclude that in patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year.

 

Cung TT et al. N Engl J Med. 2015, 373(11):1021-31. PubMed

Glycoxidized HDL, HDL enriched with oxidized phospholipids and HDL from diabetic patients inhibit platelet function.

High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). The objective of our study was to investigate the effects of in vitro glycoxidized HDL and HDL from patients with T2D on platelet aggregation and arachidonic acid signaling cascade.  We found that when compared to control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15-hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively. These glycoxidized HDL dose-dependently decreased collagen-induced platelet aggregation by binding to scavenger receptor BI (SR-BI). They also prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. Furthermore, HDL enriched with oxidized phosphatidylcholine (PC) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE, and 15-HETE in phospholipids (2.1-, 2.1- and 2.4-fold increase, respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation. Our results demonstrate that in vitro glycoxidized HDL as well as HDL from patients with T2D inhibit platelet aggregation.

 

Lê QH et al. J Clin Endocrinol Metab. 2015, 100:2006-14. PubMed

Cyclophilin D and myocardial ischemia-reperfusion injury: A fresh perspective

Reperfusion is characterized by a deregulation of ion homeostasis and generation of reactive oxygen species that enhance the ischemia-related tissue damage culminating in cell death. The mitochondrial permeability transition pore (mPTP) has been established as an important mediator of ischemia-reperfusion (IR)-induced necrotic cell death. Although a handful of proteins have been proposed to contribute in mPTP induction, cyclophilin D (CypD) remains its only bona fide regulatory component. In this review we summarize existing knowledge on the involvement of CypD in mPTP formation in general and its relevance to cardiac IR injury in specific. Moreover, we provide insights of recent advancements on additional functions of CypD depending on its interaction partners and post-translational modifications. Finally we emphasize the therapeutic strategies targeting CypD in myocardial IR injury. This article is part of a Special Issue entitled ‘Mitochondria’.

Alam MR et al. J Mol Cell Cardiol. 2014 Oct 2. Review (Team 5). Pubmed

Protective effect of the inhibition of the mitochondria-reticulum interactions during hypoxia-reoxygenation in cardiomyocytes

Recent studies indicate that calcium microdomains at the mitochondria-reticulum interface exist in the heart and are involved in the excitation-contraction coupling. So, we questioned here whether the transfer of calcium from reticulum to mitochondria might play a role in cardiomyocyte death after hypoxia-reoxygenation. We reported that during hypoxia-reoxygenation, inhibition of any partners of the IP3R1/Grp75/VDAC1/CypD calcium channeling prevented cell death by attenuating the mitochondrial calcium overload. Thus, our study suggests that depressing mitochondria-reticulum interactions and thus calcium exchanges represents a novel therapeutic strategy for treating patients suffering from myocardial infarction

Paillard M et al.,  Circulation. 2013 128:1555-65. (Team 5-3)Pubmed

Gut. 2016, 65, 144-154 Brault, C et al. Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity. PubMed

Am J Hum Genet. 2016, 98, 310-321. Jansen, J. C. et al. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. PubMed

N Engl J Med. 2016, 374, 795-797. Schiff, M., et al. SLC25A32 Mutations and Riboflavin-Responsive Exercise Intolerance. PubMed

Lancet Diabetes Endocrinol. 2016, 4:360-73. Vanholder R et al. Clinical management of the uraemic syndrome in chronic kidney disease. Pubmed

Am J Clin Nutr. 2016, 103:348-55. Egli L et al. Exercise performed immediately after fructose ingestion enhances fructose oxidation and suppresses fructose storage. Pubmed

Cancer Cell. 2015, 28:569-81. Cheng C et al. Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth. Pubmed

N Engl J Med. 2015, 373:232-42. Green JB et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. Pubmed

N Engl J Med. 2015, 373:11-22. Pi-Sunyer X et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. Pubmed

Lancet. 2015, 386:1588-98. Rossignol P et al. The double challenge of resistant hypertension and chronic kidney disease. Pubmed

N Engl J Med. 2015, 372:2387-97. Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. Pubmed

N Engl J Med. 2015, 372:1489-99. Robinson JG et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. Pubmed

Lancet Diabetes Endocrinol. 2015 3:948-57. Becker C et al. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Pubmed

Diabetes. 2015, 64:3951-62. Abdulkarim B et al. A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. Pubmed

Circulation 2015 132:27-39. Moe SM et al. Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Pubmed

Lancet. 2015, 385:331-40. Raal FJ et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Pubmed

Hum Mutat. 2015, 36:743-52. Mansour-Hendili L et al. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1. Pubmed

J Clin Endocrinol Metab. 2015, 100:E757-66. Huvenne H et al. Seven novel deleterious LEPR mutations found in early-onset obesity: a ΔExon6-8 shared by subjects from Reunion Island, France, suggests a founder effect. Pubmed

Lancet. 2014, 383:1831-43. Ortiz A et al. Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure. Pubmed

N Engl J Med. 2014, 371:1091-9. Fox K et al. Ivabradine in stable coronary artery disease without clinical heart failure. Pubmed

JAMA. 2014, 311:1515-25. Lincoff AM et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. Pubmed

N Engl J Med. 2014, 370:1702-11. STABILITY Investigators, White HD et al. Darapladib for preventing ischemic events in stable coronary heart disease. Pubmed

Free Radic Res 2014, Vol. 48, No. 10 , Pages 1232-1246. Feillet-Coudray C, et al. The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than Apocynin or Allopurinol.Pubmed

Clin Infect Dis 2014 Aug 11 pii: ciu640. Pérez-Valero I, et al. A prospective cohort study of neurocognitive function in aviremic HIV-infected patients treated with one or three antiretrovirals.Pubmed

Circulation 2014, 129: 173-185. Van Belle E, et al. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry.Pubmed

J Clin Invest 2014, 124: 1914-1927. Sala D, et al. Autophagy-regulating The TP53INP2 mediates muscle wasting and is repressed in diabetes.Pubmed

Diabetes Care 2014, 37: 1375-1383. Ortega FJ, et al. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization.Pubmed

N Engl J Med 2013, 368: 2169-2181. Legendre CM, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.Pubmed

Nature Medicine 2013, 19: 1331-1337. Wei KA, et al. Liver Hif-2alpha-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition.Pubmed

Amer J Hum Genet 2013, 93:141-9. Thauvin-Robinet C, et al. PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy.Pubmed

Diabetes 2013, 62: 3697-3708. Carobbio S, et al. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.Pubmed

BMJ 2012, 344: d7541. Beckett N, et al. Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial.Pubmed

J Clin Invest 2012, 122: 3541-3551. Jacovetti C, et al. MicroRNAs contribute to compensatory beta cell expansion during pregnancy and obesity.Pubmed

N Engl J Med 2012, 367:991-1001. De Bruyne B, et al and the FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease.Pubmed

N Engl J Med 2012, 366:1705-15. Gilard M, et al and the FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients.Pubmed

PLOS Genet 2012, 8:e1002896. Hanchate NK, et al. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann Syndrome.Pubmed

Diabetes 2012, Jul 30 [Epub ahead of print]. Volat FE, Pointud JC, Pastel E, Morio B, Sion B, Hamard G, Guichardant M, Colas R, Lefrançois-Martinez AM, Martinez A. Depressed levels of prostaglandin F2α in mice lacking Akr1b7 increase basal adiposity and predispose to diet-induced obesity.Pubmed

J Clin Endocrinol Metab 2012, 97:E575-83. Schoppet M, Hofbauer LC, Brinskelle-Schmal N, Varennes A, Goudable J, Richard M, Hawa G, Chapurlat R, Szulc P. Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: the STRAMBO study.Pubmed

Hepatology 2012, 55:1406-15. Kozakova M, et al and the RISC Investigators. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques.Pubmed

Diabetes Care 2012, 35:965-71. Riveline JP, et al and the EVADIAC Sensor Study Group. Assessment of patient-led or physician-driven continuous glucose monitoring in patients with poorly controlled type 1 diabetes using basal-bolus insulin regimens: a 1-year multicenter study.Pubmed

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