Nadia Bendridi - Academia.edu (original) (raw)

Papers by Nadia Bendridi

Archives of Cardiovascular Diseases Supplements, Jun 1, 2022

HAL (Le Centre pour la Communication Scientifique Directe), 2011

International audienc

Diabetes & Metabolism, Mar 1, 2015

Introduction Les mitochondries ont recemment emerge comme un regulateur du metabolisme energetiqu... more Introduction Les mitochondries ont recemment emerge comme un regulateur du metabolisme energetique lors des transitions nutritionnelles, et leurs interactions avec le RE (zones appelees MAM, mitochondria-associated endoplasmic reticulum membranes) comme un regulateur de l'action de l'insuline dans le foie. Neanmoins, la regulation nutritionnelle des MAM dans le foie et son role dans l'adaptation de la physiologie des mitochondries a la disponibilite en nutriments sont inconnus. Materiels et methodes L'integrite des MAM a ete etudiee, in vivo chez la souris et in vitro dans des cellules HuH7/hepatocytes primaires murins, par fractionnement cellulaire et in situ proximity ligation assay, la dynamique mitochondriale par immunofluorenscence et la respiration par oxygraphie. Resultats La periode post-prandiale reduit l'integrite des MAM dans le foie des souris. L'analyse in vitro des metabolites et/ou signaux hormonaux responsables de cette regulation a revele que le glucose est le principal regulateur nutritionnel de l'integrite des MAM dans les hepatocytes. Une augmentation des concentrations en glucose reduit les interactions inter-organites via la voie des pentoses phosphate (PP) et l'activation de la proteine PP2A, induit une fission des mitochondries et altere la respiration mitochondriale dans les hepatocytes. La prevention de la reduction de MAM, par le blocage de la voie PP-PP2A ou en surexprimant la chaperone GRP75, previent les modifications mitochondriales induites par le glucose. De maniere interessante, ce « sensing » du glucose est deficient dans le foie de souris ob/ob, caracterise par une alteration de l'integrite des MAM, une fission et dysfonction mitochondriales et une mauvaise adaptation aux transitions nutritionnelles. Conclusion Les MAM constituent un nouveau systeme de detection du glucose hepatique permettant la regulation de la dynamique et la fonction des mitochondries au cours des transitions nutritionnelles. Leurs deregulations dans le foie des souris ob/ob suggerent l'implication potentielle des MAM dans la dysfonction mitochondriale associee a l'insulinoresistance hepatique. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Hormone and Metabolic Research, May 7, 2014

Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating age... more Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan(®) on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan(®) (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan(®) treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri-glyceride production rate was markedly reduced after Niaspan(®) (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p&amp;amp;amp;lt;0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p&amp;amp;amp;lt;0.05) in the Niaspan(®) condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan(®) treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.

Journal of Hepatology, Sep 1, 2022

BACKGROUND & AIMS Hepatic insulin resistance in obesity and type 2 diabetes was recently asso... more BACKGROUND & AIMS Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions. Up to now, it is not clear if MAM miscommunication could have a causal role in hepatic insulin resistance and steatosis. We therefore aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. METHODS We analyzed hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice in a time-dependent and reversible manner, and investigated causality in hepatic metabolic alterations by expressing a specific organelle spacer or linker in mouse liver, using adenovirus. RESULTS Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in diet-induced obese mice. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type-2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. CONCLUSIONS ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could contribute to restoring metabolic homeostasis. LAY SUMMARY The literature suggests that interactions between endoplasmic reticulum (ER) and mitochondria could play a dual role in hepatic insulin resistance and steatosis during chronic obesity. The present study reappraised time-dependent regulation of hepatic ER-mitochondria interactions and calcium exchange in diet-induced obese mice and their causal role in hepatic insulin resistance and steatosis. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be improved by nutritional strategies.

Journal of Molecular Cell Biology, Feb 17, 2016

Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dy... more Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dynamics and function and in hepatic insulin action. Whereas mitochondria are important regulators of energy metabolism, the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown. 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.

HAL (Le Centre pour la Communication Scientifique Directe), 2009

ABSTRACT 5-COM (communications sans actes)

The crosstalk between the endoplasmic reticulum (ER) and mitochondria facilitates calcium transfe... more The crosstalk between the endoplasmic reticulum (ER) and mitochondria facilitates calcium transfer between these organelles, thereby maintaining the driving force for calcium into the mitochondrial matrix to modulate mitochondrial respiration. Glucose-regulated protein 75 (GRP75/mortalin) physically links ER and mitochondria through facilitating the interaction between ER-bound inositol-1,4,5-triphosphate receptors (IP3R) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane. In our study, we investigated the role of ER-mitochondrial coupling in a model of glutamate toxicity in neuronal HT22 cells that is characterized by cell death and mitochondrial dysfunction. We confirm that GRP75 determines ER-mitochondrial contact formation as shown by an in situ proximity ligation assay. Using siRNA-mediated knockdown, CRISPR/Cas9-mediated knockout and pharmacological inhibition of GRP75, we show that relieving ER-mitochondrial crosstalk preserves mitochondrial integrity and thereby prevents cell death. In response to glutamate, we observe preservation of mitochondrial morphology, attenuation of mitochondrial ROS formation and reduction of both [Ca2+]c and [Ca2+]m levels. Thus, we provide for the first time evidence that disrupting ER-mitochondrial coupling by silencing GRP75 conferred protection against oxidative stress in neuronal HT22 cells by a mechanism involving the regulation of calcium homeostasis and redox balance.

Journal of Hepatology

Circulation, Nov 19, 2019

International Journal of Molecular Sciences, 2022

Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we... more Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca2+ uncoupling is an early and reversible trigger of the cardiac dysfunction in a diet-induced mouse model of DCM. Metformin is a first-line antidiabetic drug with recognized cardioprotective effect in myocardial infarction. Whether metformin could prevent the progression of DCM remains not well understood. We therefore investigated the effect of a chronic 6-week metformin treatment on the reticulum-mitochondria Ca2+ coupling and the cardiac function in our high-fat high-sucrose diet (HFHSD) mouse model of DCM. Although metformin rescued the glycemic regulation in the HFHSD mice, it did not preserve the reticulum-mitochondria Ca2+ coupling either structurally or functionally. Metformin also did not prevent the progression towards cardiac dysfunction, i.e., cardiac hypertrophy and strain dysfunction. In summary, despite its cardioprotective rol...

Individual data values for all experiments in an Excel file. Data sets are sorted by figure. (XLS... more Individual data values for all experiments in an Excel file. Data sets are sorted by figure. (XLSX 35 kb)

Figure S1. Same as Fig. 1 with all raw data. Figure S2. Atrophying program in REDD1 KO muscles af... more Figure S1. Same as Fig. 1 with all raw data. Figure S2. Atrophying program in REDD1 KO muscles after hypoxia exposure. Figure S3. REDD1 deletion did not disrupt redox status of skeletal muscle in normoxic or hypoxic mice. Figure S4. REDD1 KO mice display an attenuated decrease in Akt/mTOR phosphorylation under energetic stress. Figure S5. REDD1 localizes in crude mitochondria after running exercise. Figure S6. REDD1 deletion does not alter the respiration capacity of isolated mitochondria. Figure S7. REDD1 overexpression does not alter citrate synthase protein expression. Figure S8. PRAS40 and mTOR localize in the crude mitochondrial fraction from skeletal muscle. Figure S9. Protein synthesis under energetic stress in human myoblasts depleted for REDD1. Figure S10. mTOR and HKII activity correlates with basal O2 consumption of myoblasts. Figure S11. Increase in mitophagy markers following intense running exercise in REDD1 KO mice. (PPTX 11020 kb)

Table S1. Classical markers of hypoxia exposure. Table S2. List of antibodies. Table S3. Primers ... more Table S1. Classical markers of hypoxia exposure. Table S2. List of antibodies. Table S3. Primers used for real-time qPCR. (DOCX 17 kb)

Tyrosine pathway regulation is host-mediated in the pea

The crosstalk between the endoplasmic reticulum (ER) and mitochondria facilitates the transfer of... more The crosstalk between the endoplasmic reticulum (ER) and mitochondria facilitates the transfer of proteins, lipids and calcium between these organelles. ER-mitochondrial coupling maintains the driving force for calcium that is released from inositol-1,4,5-triphosphate receptors (IP3R) into the mitochondrial matrix where it determines mitochondrial respiration. ER-mitochondrial contact points are built by ER-bound IP3 receptors and voltage dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane, that are connected by the chaperone glucose-regulated protein 75 (GRP75/mortalin). Enhanced mitochondrial calcium [Ca2+]m uptake, thus [Ca2+]m overload, and mitochondrial integrity are critical parameters during oxidative glutamate toxicity in neuronal HT22 cells. In our study, we investigated the role of ER-mitochondrial coupling in immortalized mouse hippocampal HT22 cells in response to glutamate-induced cell death. In these cells, we confirm that GRP75 determines ER-mitochon...