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Introduction
Publications
Publications (209)
Cellular senescence is induced by many stresses including telomere shortening, DNA damage, oxidative, or metabolic stresses. Senescent cells are stably cell cycle arrested and they secrete many factors including cytokines and chemokines. Accumulation of senescent cells promotes many age-related alterations and diseases. In this study, we investigat...
The flexibility between the wide array of hepatic functions relies on calcium (Ca2+) signalling. Indeed, Ca2+ is implicated in the control of many intracellular functions as well as intercellular communication. Thus, hepatocytes adapt their Ca2+ signalling depending on their nutritional and hormonal environment, leading to opposite cellular functio...
Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidatio...
Background & Aims:
Chronic hepatitis C virus (HCV) infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of...
Background and objectives: Metabolic flexibility is the ability of our organism to switch from fatty acid oxidation to enhanced glucose metabolism between fasted and fed states. Metabolic inflexibility induces hepatic lipid accumulation and insulin resistance, in part through a reduction of Endoplasmic Reticulum (ER)-mitochondria contact sites call...
Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): INSERM U1060
Introduction
The prevalence of type 2 diabetes (T2D) is increasing worldwide with cardiovascular complications being a leading cause of T2D-related morbi-mortality, notably diabetic cardiomyopathy (DCM). The involvement of...
Introduction
Diabetic cardiomyopathy, as a major complication of type 2 diabetes (T2D), shows a rising prevalence nowadays. Reticulum-mitochondria Ca2+ uncoupling was recently reported as an early but reversible trigger of cardiac dysfunction using a diet-induced murine model of DCM with heart failure and preserved ejection fraction (HFpEF). Metfor...
Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a F...
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 myocar...
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 rol...
Résumé
Les interactions structurales et fonctionnelles entre le réticulum endoplasmique et la mitochondrie, au niveau des points de contact appelés MAMs (Mitochondria-associated membranes), exercent un contrôle sur l’homéostasie cellulaire. Récemment, de nouvelles fonctions dans la détection des signaux nutritionnels et hormonaux leur confèrent un...
Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calciu...
We have determined the lipid, protein and miRNA composition of skeletal muscle (SkM)-released extracellular vesicles (ELVs) from Ob/ob (OB) vs wild-type (WT) mice. The results showed that atrophic insulin-resistant OB-SkM released less ELVs than WT-SkM, highlighted by a RAB35 decrease and an increase in intramuscular cholesterol content. Proteomic...
Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular...
The authors and the Cells Editorial Office would like to add the section “Materials and Methods”, which was missing in the original version [...]
In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial...
Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms occurring in the different regions of the intestine, adult male mice were fed a high-fat-high sucrose (HFS) diet for 8 days and treated with metform...
Mitochondrial diseases are genetic disorders leading to an impaired mitochondrial function and resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, the fast-twitch skeletal muscle-specific Tfam deletion (Tfam KO) leads to d...
In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatoc...
Introduction
The prevalence of type 2 diabetes (T2D) is increasing dramatically in our modern world. Cardiovascular complications are the leading cause of T2D-related morbi-mortality, notably diabetic cardiomyopathy (DCM). This cardiac dysfunction is characterized by hypertrophy and diastolic dysfunction. DCM animal models are required to better de...
Over the course of diet-induced obesity (DIO), adipose tissue macrophage (ATM) populations transition from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that the Interferon Regulatory Factor (IRF)-5 is a key molecular switch mediating repression of macrophage oxidative capacity early in D...
Obesity 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 p...
Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms that occur in the different regions of the intestinal tract in response to metformin treatment, adult male mice were fed a high-fat-high sucrose (HF...
Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel an...
Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca ²⁺ ) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophi...
Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum–mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat hi...
The 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 path...
Following a prolonged exposure to hypoxia–reoxygenation, a partial disruption of the ER-mitochondria tethering by mitofusin 2 (MFN2) knock-down decreases the Ca2+ transfer between the two organelles, limits mitochondrial Ca2+ overload and prevents the Ca2+-dependent opening of the mitochondrial permeability transition pore, i.e., limits cardiomyocy...
Aims/hypothesisDisrupted intracellular Ca2+ handling is known to play a role in diabetic cardiomyopathy but it has also been postulated to contribute to obesity- and type 2 diabetes-associated skeletal muscle dysfunction. Still, there is so far very limited functional insight into whether, and if so to what extent, muscular Ca2+ homeostasis is affe...
Introduction
Type 2 diabetic cardiomyopathy has been linked to Ca2+ signaling alterations, notably a decreased mitochondrial Ca2+ uptake. Recent discovery of Ca2+ microdomains between cardiac mitochondria and reticulum launched a new investigation avenue for cardiometabolic diseases.
Objective
Hereby, we aimed to investigate if the mitochondrial C...
We have determined whether orange juice-derived nanovesicles (ONV) could be used for the treatment of obesity-associated intestinal complications. ONV were characterized by lipidomic, metabolomic, electron microscopy. In vitro, intestinal barrier (IB= Caco-2+HT-29-MTX) were treated with ONV and co-cultured with adipocytes to monitor IB fat release....
Introduction
Determinants of health and diseases in humans involve complex interactions between diet, gut microbiota and host metabolism. The liver is a major organ that coordinates host adaptations to environmental factors. Mitochondria and endoplasmic reticulum tightly regulate liver nutrient sensing and metabolic adaptations, shaping its metabol...
Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets o...
Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high-energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57Bl...
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...
Interactions between endoplasmic reticulum (ER) and mitochondria are key components of essential cellular functions. Indeed, these membrane appositions are necessary for proper Ca²⁺ transfer from ER to mitochondria, to regulate lipid metabolism, apoptosis, and inflammation. We report that the ER protein WFS1 interacts with the neuronal calcium sens...
Introduction
Diabetic cardiomyopathy has been linked to Ca2 + signaling alterations, notably a decreased mitochondrial Ca2 + uptake. Uncovering the changes occurring at Ca2 + microdomains between reticulum and mitochondria in the heart has launched a new area of investigation for cardiometabolic diseases.
Objective
We here aimed to study if the im...
Discipline
Expérimental/mécanismes cellulaires et moléculaires.
Introduction et but de l’étude
La prévalence de l’obésité, de la stéatose hépatique non alcoolique et de la résistance à l’insuline augmente rapidement et devient un problème majeur de santé publique. L’obésité et ses complications s’accompagnent souvent d’une inflammation et d’un str...
Inflammation and oxidative stress are thought to be involved in, or associated with, the development of obesity, dyslipidemia, hepatic steatosis, and insulin resistance. This work was designed to determine the evolution of inflammation and oxidative stress during onset and progression of hepatic steatosis and glucose intolerance. Seventy‐five male...
Wolfram syndrome is a childhood onset rare genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy unavoidably progressing towards legal blindness before the age of 20. Here we show that WFS1 forms a complex with Neuronal Calcium Sensor 1 (NCS1) and IP3R to promote ER-mitochondrial Ca2+ transfer. In addition, we report that NCS...
Introduction et but de l’étude
En condition non-inflammatoire, le monoxyde d’azote (NO) produit par l’enzyme NO synthase endothéliale (eNOS) joue un rôle majeur dans le maintien de l’homéostasie hépatique du glucose [1], [2]. La mitochondrie étant une cible du NO, nous avons posé l’hypothèse que celui-ci pouvait être impliqué dans la régulation des...
Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca ²⁺ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we sho...
Background:
Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a...
Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca2+) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linkage may reduce Ca2+ uptake into
mitochondria, while f...
Cardiovascular diseases associated with metabolic syndrome remain frequent and still disabling for patients. The uncovering of Ca2+ microdomains between mitochondria and reticulum (SR) in the heart has launched a new area of investigation for cardiometabolic diseases.
Here, we sought to determine the structural and functional role of the SR-mitocho...
Cardiovascular diseases associated with metabolic syndrome remain frequent and still disabling for patients. The uncovering of Ca²⁺ microdomains between mitochondria and reticulum (SR) in the heart has launched a new area of investigation for cardiometabolic diseases.
Here, we sought to determine the structural and functional role of the SR-mitocho...
The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving. MAMs allow the exchange between both organelles of lipids,...
Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main...
The crosstalk between different organelles allows for the exchange of proteins, lipids and ions. Endoplasmic reticulum (ER) and mitochondria are physically linked and signal through the mitochondria-associated membrane (MAM) to regulate the transfer of Ca2+ from ER stores into the mitochondrial matrix, thereby affecting mitochondrial function and i...
Whereas reactive oxygen species (ROS) can have opposite impacts on insulin signaling, they have mainly been associated with mitochondrial dysfunction in skeletal muscle. We analyzed the relationship between these three features in skeletal muscle of senescence accelerated mice (SAM) prone (P8), which are characterized by enhanced oxidative stress c...
Although mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and disrupted lipid and calcium (Ca²⁺) homeostasis are classically associated with both insulin resistance and β-cell dysfunction in type 2 diabetes mellitus (T2DM), the interplay between these metabolic stresses is less known. Both organelles interact through contact points kno...
Type 2 diabetes develops when beta cells are not able to fulfill insulin needs. The role of the endoplasmic reticulum–mitochondria junction in coordinating the functions of these two organelles throughout the natural history of type 2 diabetes is determinant and may explain the alterations of insulin biosynthesis. Our goal was to study endoplasmic...
Mitofusin-2 and VDAC-1 expression in beta cells.
Representative immunofluorescence analysis of a pancreatic section with a slide scanner from a 46-year-old donor with type 2 diabetes (nPOD# 6133) and a 30-year-old non-diabetic donor (nPOD# 6235) for insulin,MFN-2,VDAC-1 and merge The scale bar corresponds to 50 microns.
(EPS)
ITPR2 mRNA expression is increased in diabetic islets.
In situ hybridization was performed in nPOD sample # 6255 with ITPR2 probe (A) a positive probe PPIB (B) and negative probe DapB (C). The scale bar indicates 50 microns. Morphometric analysis of ITPR2 mRNA expression in islet cells were performed in 6 donors with type 2 diabetes (closed circles...
Morphometric analyses of VDAC-1 expression in beta cells.
Immunofluorescence studies for VDAC-1 expression in beta cells were performed with a slide scanner in 11 donors with type 2 diabetes (closed circles) compared to 8 donors without history of diabetes (open circles). Each circle corresponds to the mean expression level for a single islet. The...
Absence of correlation between the number of IP3R2- VDAC1 complexes and peripheral C-peptide levels.
Mean results of in situ proximity ligation assay per islet cells do not correlate with peripheral C-peptide levels both in donor with diabetes (closed symbols) or controls (open symbols).
(EPS)
IP3R2 colocalizes with beta cells.
Representative immunofluorescence confocal analysis of a pancreatic section from a 55-year-old diabetic donor (nPOD# 6255) stained for insulin (green), glucagon (white) and IP3R2 (red). IP3R2 (A) is predominantly expressed in beta cells identified by insulin staining (B)and less in alpha cells stained for glucagon...
Representative IP3R2 immunofluorescence staining.
Expression patterns of IP3R2 and insulin of pancreatic islets from 12 donors with type 2 diabetes and 9 controls. The scale bar indicates 50 microns.
(EPS)
TOM20 expression in beta cells.
Representative immunofluorescence analysis in panel A with a slide scanner of pancreatic islets from a 55-year-old diabetic donor (nPOD# 6255) and a 58-year-old non diabetic donor (nPOD# 6290) for insulin (A), TOM20 (B) and merge (C). The scale bar indicates 50 microns. Panel B shows the morphometric immunofluorescen...
Morphometric analysis of mitofusin 2 expression in beta cells.
Immunofluorescence studies for MFN-2 expression in beta cells were performed with a slide scanner in 11 donors with type 2 diabetes (closed circles) compared to 9 donors without history of diabetes (open circles). Each circle corresponds to the mean expression level for a single islet....
The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber...