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Giovanni BENARD




Principal Investigator

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Actual position:
Chargé de Recherche CNRS

Laboratoire Maladies Rares
Génétique et Métabolisme-INSERM U1211

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25 publication(s) since Août 2005:


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The indicated IF have been collected by the Web of Sciences in


05/06/2018 | Cell Rep   IF 7.8
Ubiquitin-Dependent Degradation of Mitochondrial Proteins Regulates Energy Metabolism.
Lavie J, De Belvalet H, Sonon S, Ion AM, Dumon E, Melser S, Lacombe D, Dupuy JW, Lalou C, Benard G

Abstract:
The ubiquitin proteasome system (UPS) regulates many cellular functions by degrading key proteins. Notably, the role of UPS in regulating mitochondrial metabolic functions is unclear. Here, we show that ubiquitination occurs in different mitochondrial compartments, including the inner mitochondrial membrane, and that turnover of several metabolic proteins is UPS dependent. We specifically detailed mitochondrial ubiquitination and subsequent UPS-dependent degradation of succinate dehydrogenase subunit A (SDHA), which occurred when SDHA was minimally involved in mitochondrial energy metabolism. We demonstrate that SDHA ubiquitination occurs inside the organelle. In addition, we show that the specific inhibition of SDHA degradation by UPS promotes SDHA-dependent oxygen consumption and increases ATP, malate, and citrate levels. These findings suggest that the mitochondrial metabolic machinery is also regulated by the UPS.




09/11/2016 | Nature   IF 43.1
A cannabinoid link between mitochondria and memory.
Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, Zottola AC, Delamarre A, Cannich A, Vincent P, Varilh M, Robin LM, Terral G, Garcia-Fernandez MD, Colavita M, Mazier W, Drago F, Puente N, Reguero L, Elezgarai I, Dupuy JW, Cota D, Lopez-Rodriguez ML, Barreda-Gomez G, Massa F, Grandes P, Benard G, Marsicano G

Abstract:
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Galphai protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.




06/2016 | Neurobiol Dis   IF 5.2
MitoBrain, Putting energy into the brain.
Benard G, Bezard E, Marsicano G, Pouvreau S

Abstract:





2016 | front physiol   IF 3.2
Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration.
Mendizabal-Zubiaga J, Melser S, Benard G, Ramos A, Reguero L, Arrabal S, Elezgarai I, Gerrikagoitia I, Suarez J, Rodriguez De Fonseca F, Puente N, Marsicano G, Grandes P

Abstract:
The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1), where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles. Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB1 -KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Delta(9)-THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1 -KO mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1 -KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1 -WT and CB1 -KO. CB1 -KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant difference was observed in the Sdha and Cox4i1 expression, between CB1 -WT and CB1 -KO. In conclusion, CB1 receptors in skeletal and myocardial muscles are predominantly localized in mitochondria. The activation of mtCB1 receptors may participate in the mitochondrial regulation of the oxidative activity probably through the relevant enzymes implicated in the pyruvate metabolism, a main substrate for TCA activity.




2015 | Biochim Biophys Acta   IF 3.7
Mitochondrial degradation and energy metabolism
Melser S, Lavie J, Benard G

Abstract:
Mitochondria are intracellular power plants that feed most eukaryotic cells with the ATP produced by the oxidative phosphorylation (OXPHOS). Mitochondrial energy production is controlled by many regulatory mechanisms. The control of mitochondrial mass through both mitochondrial biogenesis and degradation has been proposed to be one of the most important regulatory mechanisms. Recently, autophagic degradation of mitochondria has emerged as an important mechanism involved in the regulation of mitochondrial quantity and quality. In this review, we highlight the intricate connections between mitochondrial energy metabolism and mitochondrial autophagic degradation by showing the importance of mitochondrial bioenergetics in this process and illustrating the role of mitophagy in mitochondrial patho-physiology. Furthermore, we discuss how energy metabolism could coordinate the biogenesis and degradation of this organelle.




07/2014 | Mol Metab   IF 6.2
Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G

Abstract:
Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false positive and/or false negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions.




07/2014 | Mol Metab   IF 6.2
Studying mitochondrial CB1 receptors: Yes we can.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G

Abstract:





07/05/2013 | Cell Metab   IF 22.4
Rheb Regulates Mitophagy Induced by Mitochondrial Energetic Status
Melser S, Hebert-Chatelain E, Lavie J, et al., Benard G

Abstract:
Mitophagy has been recently described as a mechanism of elimination of damaged organelles. Although the regulation of the amount of mitochondria is a core issue concerning cellular energy homeostasis, the relationship between mitochondrial degradation and energetic activity has not yet been considered. Here, we report that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. Upon high oxidative phosphorylation activity, we found that the small GTPase Rheb is recruited to the mitochondrial outer membrane. This mitochondrial localization of Rheb promotes mitophagy through a physical interaction with the mitochondrial autophagic receptor Nix and the autophagosomal protein LC3-II. Thus, Rheb-dependent mitophagy contributes to the maintenance of optimal mitochondrial energy production. Our data suggest that mitochondrial degradation contributes to a bulk renewal of the organelle in order to prevent mitochondrial aging and to maintain the efficiency of oxidative phosphorylation.




01/05/2013 | Biol Psychiatry   IF 11.5
Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance.
Dubreucq S, Durand A, Matias I, Benard G, Richard E, Soria-Gomez E, Glangetas C, Groc L, Wadleigh A, Massa F, Bartsch D, Marsicano G, Georges F, Chaouloff F

Abstract:
BACKGROUND: We have shown that the endogenous stimulation of cannabinoid type-1 (CB(1)) receptors is a prerequisite for voluntary running in mice, but the precise mechanisms through which the endocannabinoid system exerts a tonic control on running performance remain unknown. METHODS: We analyzed the respective impacts of constitutive/conditional CB(1) receptor mutations and of CB(1) receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB(1) receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]-CB(1)(+)/(+)) and mutant (GABA-CB(1)(-)/(-)) mice for CB(1) receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA-CB(1)(+)/(+) and GABA-CB(1)(-)/(-) mice. RESULTS: Conditional deletion of CB(1) receptors from brain GABA neurons, but not from several other neuronal populations or from astrocytes, decreased wheel-running performance in mice. The inhibitory consequences of either the systemic or the intra-VTA administration of CB1 receptor antagonists on running behavior were abolished in GABA-CB(1)(-)/(-) mice. The absence of CB1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running. CONCLUSIONS: This study provides evidence that CB(1) receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB(1) receptors located on GABAergic neurons impede negative consequences of voluntary exercise on VTA DA neuronal activity. These results position the endocannabinoid control of inhibitory transmission as a prerequisite for wheel-running performance in mice.




03/2013 | Antioxid Redox Signal   IF 5.8
Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis
Jose C, Melser S, Benard G, Rossignol R

Abstract:
Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are a part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored, and it has become critical to decipher the stimuli and the underlying molecular pathways. Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, Endoplasmic Reticulum stress, genotoxic stress, or environmental toxic insults. Delayed adaptations of mitochondrial form, composition, and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma, or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Little is known on the signals and downstream pathways that govern mitochondrial adaptations and transformations. Few adaptative loops, including redox sensors, kinases, and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Mitoplasticity could play a protective role against aging, diabetes, cancer, or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer