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1. The Metabolomic Signature of Opa1 Deficiency in Rat Primary Cortical Neurons Shows Aspartate/Glutamate Depletion and Phospholipids Remodeling

Author

Pascale Belenguer, Juan Manuel Chao de la Barca, Guy Lenaers, Guillaume Tcherkez, Gilles Simard, Laetitia Arnauné-Pelloquin, Pascal Reynier, Olga Iuliano, Cinzia Bocca, Macarena S. Arrázola, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie des Plantes (IBP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), LENAERS, Guy, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
0301 basic medicine, endocrine system, [SDV]Life Sciences [q-bio], Primary Cell Culture, Phospholipid, Down-Regulation, Glutamic Acid, lcsh:Medicine, Article, GTP Phosphohydrolases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Downregulation and upregulation, Optic Atrophy, Autosomal Dominant, Animals, Humans, RNA, Small Interfering, Threonine, lcsh:Science, Cells, Cultured, Phospholipids, ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Neurons, Aspartic Acid, Multidisciplinary, Chemistry, lcsh:R, Glutamate receptor, RNA, Embryo, Mammalian, eye diseases, Rats, Cell biology, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, mitochondrial fusion, Female, lcsh:Q, Sphingomyelin, 030217 neurology & neurosurgery
Abstract

Pathogenic variants of OPA1, which encodes a dynamin GTPase involved in mitochondrial fusion, are responsible for a spectrum of neurological disorders sharing optic nerve atrophy and visual impairment. To gain insight on OPA1 neuronal specificity, we performed targeted metabolomics on rat cortical neurons with OPA1 expression inhibited by RNA interference. Of the 103 metabolites accurately measured, univariate analysis including the Benjamini-Hochberg correction revealed 6 significantly different metabolites in OPA1 down-regulated neurons, with aspartate being the most significant (p 2cum = 0.65) and a low risk of over-fitting (permQ2 = −0.16, CV-ANOVA p-value 0.036). Amongst the 46 metabolites contributing the most to the metabolic signature were aspartate, glutamate and threonine, which all decreased in OPA1 down-regulated neurons, and lysine, 4 sphingomyelins, 4 lysophosphatidylcholines and 32 phosphatidylcholines which were increased. The phospholipid signature may reflect intracellular membrane remodeling due to loss of mitochondrial fusion and/or lipid droplet accumulation. Aspartate and glutamate deficiency, also found in the plasma of OPA1 patients, is likely the consequence of respiratory chain deficiency, whereas the glutamate decrease could contribute to the synaptic dysfunction that we previously identified in this model.

Published
2019
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2. Mitochondria in Developmental and Adult Neurogenesis

Author

Laetitia Arnauné-Pelloquin, Marie-Christine Miquel, Noélie Davezac, Lionel Moulédous, Marion Szelechowski, Pascale Belenguer, Macarena S. Arrázola, Claire Rampon, Trinovita Andraini, Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, and Department of Physiology, Faculty of Medicine, University of Indonesia

Subjects
Adult, 0301 basic medicine, Neurogenesis, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Oxidative phosphorylation, Mitochondrion, Biology, Development, Toxicology, Adult neurogenesis, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Animals, Humans, Glycolysis, Neurochemistry, Neurons, General Neuroscience, Cell Differentiation, Mitochondrial morphology, Neural stem cell, Mitochondria, 030104 developmental biology, Neuroscience, 030217 neurology & neurosurgery, Function (biology)
Abstract

International audience; Generation of new neurons is a tightly regulated process that involves several intrinsic and extrinsic factors. Among them, a metabolic switch from glycolysis to oxidative phosphorylation, together with mitochondrial remodeling, has emerged as crucial actors of neurogenesis. However, although accumulating data raise the importance of mitochondrial morphology and function in neural stem cell proliferation and differentiation during development, information regarding the contribution of mitochondria to adult neurogenesis processes remains limited. In the present review, we discuss recent evidence covering the importance of mitochondrial morphology, function, and energy metabolism in the regulation of neuronal development and adult neurogenesis, and their impact on memory processes.

Published
2019
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3. Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential

Author

Noélie Davezac, Jean-Michel Peyrin, Pascale Belenguer, Marion Szelechowski, Anne Thouard, Daniel Gonzalez-Dunia, Cécile A. Ferré, Marie-Christine Miquel, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM, Centre National de la Recherche Scientifique, INSERM Transfert CoPoC Fund, European Research Area Networks (ERA-NET) Network of European Funding for Neuroscience Research (NEURON) MicroDeg, [ANR-12-EMMA-0016-01], Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE16-0013,MitoX,Analyse des mécanismes moléculaires et cellulaires des propriétés neuroprotectrices d'une protéine virale(2016)

Subjects
0301 basic medicine, Signal peptide, Mutant, Blotting, Western, Green Fluorescent Proteins, Molecular Sequence Data, Nuclear Localization Signals, Biology, Mitochondrion, Biochemistry, Neuroprotection, Green fluorescent protein, 03 medical and health sciences, Viral Proteins, Chlorocebus aethiops, Genetics, Animals, Humans, Amino Acid Sequence, Nuclear export signal, Borna disease virus, Molecular Biology, Cells, Cultured, Neurons, Aspartic Acid, Sequence Homology, Amino Acid, subcellular addressing, Subcellular localization, Fusion protein, Axons, Mitochondria, 030104 developmental biology, HEK293 Cells, Microscopy, Fluorescence, COS Cells, Mutation, neuroprotection, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], nuclear export, Biotechnology
Abstract

International audience; To favor their replication, viruses express proteins that target diverse mammalian cellular pathways. Due to the limited size of many viral genomes, such proteins are endowed with multiple functions, which require targeting to different subcellular compartments. One salient example is the X protein of Borna disease virus, which is expressed both at the mitochondria and in the nucleus. Moreover, we recently demonstrated that mitochondrial X protein is neuroprotective. In this study, we sought to examine the mechanisms whereby the X protein transits between subcellular compartments and to define its localization signals, to enhance its mitochondrial accumulation and thus, potentially, its neuroprotective activity. We transfected plasmids expressing fusion proteins bearing different domains of X fused to enhanced green fluorescent protein (eGFP) and compared their subcellular localization to that of eGFP. We observed that the 5-16 domain of X was responsible for both nuclear export and mitochondrial targeting and identified critical residues for mitochondrial localization. We next took advantage of these findings and constructed mutant X proteins that were targeted only to the mitochondria. Such mutants exhibited enhanced neuroprotective properties in compartmented cultures of neurons grown in microfluidic chambers, thereby confirming the parallel between mitochondrial accumulation of the X protein and its neuroprotective potential.-Ferre C. A., Davezac, N., Thouard, A., Peyrin, J. M., Belenguer, P., Miquel, M.-C., Gonzalez-Dunia, D., Szelechowski, M. Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential. FASEB J. 30, 1523-1533 (2016). www.fasebj.org

Published
2016
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4. Loss of Msp1p in Schizosaccharomyces pombe induces a ROS-dependent nuclear mutator phenotype that affects mitochondrial fission genes

Author

Pascale Belenguer, Laurent J. Emorine, Nathalie Bonnefoy, Christopher J. Herbert, Farnoosh Khosrobakhsh, Laetitia Arnauné-Pelloquin, Thomas Delerue, Adrien Dedieu, Marlène Daloyau, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biogenèse et fonctionnement des complexes OXPHOS mitochondriaux (BIOMIT), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Dynamins, 0301 basic medicine, Mitochondrial DNA, [SDV]Life Sciences [q-bio], Biophysics, GTPase, mitochondrial DNA, Mitochondrion, Biology, DNA, Mitochondrial, Mitochondrial Dynamics, Biochemistry, GTP Phosphohydrolases, law.invention, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, law, Gene Expression Regulation, Fungal, Schizosaccharomyces, Genetics, mitochondrial fission and fusion, Molecular Biology, Gene, Cell Biology, biology.organism_classification, Mitochondria, Phenotype, 030104 developmental biology, mitochondrial fusion, Schizosaccharomyces pombe, Suppressor, Mitochondrial fission, Schizosaccharomyces pombe Proteins, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract

Mitochondria continually fuse and divide to dynamically adapt to changes in metabolism and stress. Mitochondrial dynamics are also required for mitochondrial DNA (mtDNA) integrity; however, the underlying reason is not known. In this study, we examined the link between mitochondrial fusion and mtDNA maintenance in Schizosaccharomyces pombe, which cannot survive without mtDNA, by screening for suppressors of the lethality induced by loss of the dynamin-related large GTPase Msp1p. Our findings reveal that inactivation of Msp1p induces a ROS-dependent nuclear mutator phenotype that affects mitochondrial fission genes involved in suppressing mitochondrial fragmentation and mtDNA depletion. This indicates that mitochondrial fusion is crucial for maintaining the integrity of both mitochondrial and nuclear genetic information. Furthermore, our study suggests that the primary roles of Msp1p are to organize mitochondrial membranes, thus making them competent for fusion, and maintain the integrity of mtDNA.

Published
2016
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5. Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

Author

Sebastien Magifico, Pascale Belenguer, Benjamin Lassus, Jean-Michel Peyrin, Marie-Christine Miquel, Sandra Pignon, Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Vieillissement Cellulaire Intégré et Inflammation (VCII), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), HAL-UPMC, Gestionnaire, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Multidisciplinary, Cell, Context (language use), Anatomy, Rotenone, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, medicine.anatomical_structure, chemistry, nervous system, medicine, Mitochondrial fission, Neuron, Fragmentation (cell biology), Neuroscience, Axonal degeneration, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

In chronic neurodegenerative syndromes, neurons progressively die through a generalized retraction pattern triggering retrograde axonal degeneration toward the cell bodies, which molecular mechanisms remain elusive. Recent observations suggest that direct activation of pro-apoptotic signaling in axons triggers local degenerative events associated with early alteration of axonal mitochondrial dynamics. This raises the question of the role of mitochondrial dynamics on both axonal vulnerability stress and their implication in the spreading of damages toward unchallenged parts of the neuron. Here, using microfluidic chambers, we assessed the consequences of interfering with OPA1 and DRP1 proteins on axonal degeneration induced by local application of rotenone. We found that pharmacological inhibition of mitochondrial fission prevented axonal damage induced by rotenone, in low glucose conditions. While alteration of mitochondrial dynamics per se did not lead to spontaneous axonal degeneration, it dramatically enhanced axonal vulnerability to rotenone, which had no effect in normal glucose conditions, and promoted retrograde spreading of axonal degeneration toward the cell body. Altogether, our results suggest a mitochondrial priming effect in axons as a key process of axonal degeneration. In the context of neurodegenerative diseases, like Parkinson’s and Alzheimer’s, mitochondria fragmentation could hasten neuronal death and initiate spatial dispersion of locally induced degenerative events.

Published
2016
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6. Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis

Author

Anne Devin, Ambre M. Bertholet, Noélie Davezac, Pascal Reynier, Pascale Belenguer, Marlène Daloyau, Anne Galinier, Aurélie M. C. Millet, Bernd Wissinguer, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Programmed cell death, Pathology, medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Biology, medicine.disease_cause, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Downregulation and upregulation, medicine, Research Articles, chemistry.chemical_classification, Reactive oxygen species, General Neuroscience, medicine.disease, eye diseases, 3. Good health, Cell biology, 030104 developmental biology, chemistry, Neurology (clinical), Haploinsufficiency, 030217 neurology & neurosurgery, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

International audience; OBJECTIVE: OPA1 mutations cause protein haploinsufficiency leading to dominant optic atrophy (DOA), an incurable retinopathy with variable severity. Up to 20% of patients also develop extraocular neurological complications. The mechanisms that cause this optic atrophy or its syndromic forms are still unknown. After identifying oxidative stress in a mouse model of the pathology, we sought to determine the consequences of OPA1 dysfunction on redox homeostasis.METHODS: Mitochondrial respiration, reactive oxygen species levels, antioxidant defenses, and cell death were characterized by biochemical and in situ approaches in both in vitro and in vivo models of OPA1 haploinsufficiency.RESULTS: A decrease in aconitase activity suggesting an increase in reactive oxygene species and an induction of antioxidant defenses was observed in cortices of a murine model as well as in OPA1 downregulated cortical neurons. This increase is associated with a decline in mitochondrial respiration in vitro. Upon exogenous oxidative stress, OPA1-depleted neurons did not further exhibit upregulated antioxidant defenses but were more sensitive to cell death. Finally, low levels of antioxidant enzymes were found in fibroblasts from patients supporting their role as modifier factors.INTERPRETATION: Our study suggests that the pro-oxidative state induced by OPA1 loss may contribute to DOA pathogenesis and that differences in antioxidant defenses can explain the variability in expressivity. Furthermore, antioxidants may be used as therapy as they could prevent or delay DOA symptoms in patients.

Published
2016
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7. Mitochondrial Reshaping Accompanies Neural Differentiation in the Developing Spinal Cord

Author

Pascale Belenguer, Sophie Bel-Vialar, Valérie Mils, Fabienne Pituello, Stéphanie Bosch, Marie-Christine Miquel, Julie Roy, Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cellular differentiation, Neurogenesis, Population, lcsh:Medicine, Context (language use), Chick Embryo, Biology, Mitochondrion, Mice, Neural Stem Cells, medicine, Animals, Humans, education, lcsh:Science, Neurons, education.field_of_study, Multidisciplinary, [SCCO.NEUR]Cognitive science/Neuroscience, lcsh:R, Neural tube, Cell Differentiation, Anatomy, Neural stem cell, Cell biology, Mitochondria, medicine.anatomical_structure, mitochondrial fusion, Spinal Cord, lcsh:Q, Nerve Net, Research Article, HeLa Cells
Abstract

International audience; Mitochondria, long known as the cell powerhouses, also regulate redox signaling and arbitrate cell survival. The organelles are now appreciated to exert additional critical roles in cell state transition from a pluripotent to a differentiated state through balancing glycolytic and respiratory metabolism. These metabolic adaptations were recently shown to be concomi-tant with mitochondrial morphology changes and are thus possibly regulated by contingencies of mitochondrial dynamics. In this context, we examined, for the first time, mitochondrial network plasticity during the transition from proliferating neural progenitors to post-mitotic differentiating neurons. We found that mitochondria underwent morphological reshaping in the developing neural tube of chick and mouse embryos. In the proliferating population, mitochondria in the mitotic cells lying at the apical side were very small and round, while they appeared thick and short in interphase cells. In differentiating neurons, mi-tochondria were reorganized into a thin, dense network. This reshaping of the mitochondrial network was not specific of a subtype of progenitors or neurons, suggesting that this is a general event accompanying neurogenesis in the spinal cord. Our data shed new light on the various changes occurring in the mitochondrial network during neurogenesis and suggest that mitochondrial dynamics could play a role in the neurogenic process.

Published
2015
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8. Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats

Author

Luc Pénicaud, Xavier Fioramonti, Michel Rigoulet, Christophe Guissard, Pascale Belenguer, Emmanuelle Nédélec, Danielle Bailbe, Camille Allard, Corinne Barreau, Géraldine Offer, Cécile Tourrel-Cuzin, Bénédicte Salin, Corinne Leloup, Lionel Carneiro, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ministere de la Recherche et de la Technologie, Agence Nationale de la Recherche [ANR-06-PHYSIO-Oox], Alfediam (Prize Merck-Lipha), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Institut de biochimie et génétique cellulaires ( IBGC ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Biologie cellulaire et moléculaire du contrôle de la prolifération ( BCMCP ), and Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, Energy-Generating Resources, nervous-system, Physiology, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Clinical Biochemistry, neurons, Mitochondrion, Biochemistry, involvement, Energy homeostasis, DNM1L, 0302 clinical medicine, Insulin-Secreting Cells, Insulin Secretion, Insulin, General Environmental Science, 2. Zero hunger, chemistry.chemical_classification, 0303 health sciences, Transport protein, Mitochondria, Protein Transport, Hypothalamus, Gene Knockdown Techniques, Mitochondrial Membranes, Mitochondrial fission, RNA Interference, Dynamins, medicine.medical_specialty, endocrine system, brain, mechanism, Carbohydrate metabolism, Biology, 03 medical and health sciences, Oxygen Consumption, Internal medicine, expression, medicine, Animals, Rats, Wistar, Molecular Biology, energy homeostasis, 030304 developmental biology, Reactive oxygen species, Appetite Regulation, Arcuate Nucleus of Hypothalamus, Cell Biology, islet blood-flow, Rats, Endocrinology, Glucose, chemistry, Ventromedial Hypothalamic Nucleus, General Earth and Planetary Sciences, activation, Reactive Oxygen Species, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, insulin-secretion
Abstract

International audience; AIMS: Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing. RESULTS: Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expression was transiently knocked down by intra-ventromedial hypothalamus (VMH) DRP1 siRNA (siDRP1) injection. 72 h post siRNA injection, brain intracarotid glucose induced insulin secretion, and VMH glucose infusion-induced refeeding decrease were measured, as well as mROS production. The SiDRP1 rats decreased mROS and impaired intracarotid glucose injection-induced insulin secretion. In addition, the VMH glucose infusion-induced refeeding decrease was lost in siDRP1 rats. Finally, mitochondrial function was evaluated by oxygen consumption measurements after DRP1 knock down. Although hypothalamic mitochondrial respiration was not modified in the resting state, substrate-driven respiration was impaired in siDRP1 rats and associated with an alteration of the coupling mechanism. INNOVATION AND CONCLUSION: Collectively, our results suggest that glucose-induced DRP1-dependent mitochondrial fission is an upstream regulator for mROS signaling, and consequently, a key mechanism in hypothalamic glucose sensing. Thus, for the first time, we demonstrate the involvement of DRP1 in physiological regulation of brain glucose-induced insulin secretion and food intake inhibition. Such involvement implies DRP1-dependent mROS production.

Published
2012
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9. The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms

Author

Manuel Rojo, Thomas Landes, Laetitia Arnauné-Pelloquin, Delphine Courilleau, Pascale Belenguer, Laurent J. Emorine, Institut de biochimie et génétique cellulaires (IBGC), and Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Dynamins, endocrine system, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Mitochondrion, Biochemistry, Retinal ganglion, Mitochondrial apoptosis-induced channel, GTP Phosphohydrolases, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Genetics, Humans, Protein Structure, Quaternary, Inner mitochondrial membrane, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dynamin, 0303 health sciences, Scientific Reports, Membrane Proteins, eye diseases, Mitochondria, Cell biology, mitochondrial fusion, 030220 oncology & carcinogenesis, Mitochondrial fission, sense organs, HeLa Cells, Protein Binding
Abstract

Opa1 modulates mitochondrial fusion, cristae structure and apoptosis. The relationships between these functions and autosomal dominant optic atrophy, caused by mutations in Opa1, are poorly defined. We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. Our results uncover a direct link between Opa1 on the inner mitochondrial membrane and the apoptotic machinery on the outer membrane that modulates fusion and cristae structure by separate mechanisms. These findings might help to unravel optic atrophy aetiology as retinal ganglion cells are particularly prone to hypoxia, an inductor of Bnip3 expression.

Published
2010

10. The fission yeast Nim1/Cdr1 kinase: A link between nutritional state and cell cycle control

Author

Laetitia Pelloquin, Marie-Louise Oustrin, Bernard Ducommun, Pascale Belenguer, Véronique Baldin, Laboratoire de Pharmacologie et de Toxicologie Fondamentales (LPTF), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
biology, Kinase, Cell growth, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cell cycle, biology.organism_classification, Cell biology, Wee1, Schizosaccharomyces pombe, biology.protein, Nuclear protein, Cell Cycle Protein, Mitosis, ComputingMilieux_MISCELLANEOUS
Abstract

Close connections appear to exist between extra-cellular signals that regulate cell proliferation and the protein kinases that control the cell cycle machinery. The fission yeast nim1 kinase is an inducer of cdc2 kinase activity acting through the inhibition of wee1 kinase. Nim1 function is required for a correct cellular response to nutritional starvation. In the absence of nim1, starved cells are unable to decrease their size at mitosis, to arrest their cycle in G1 and to enter G0. Here, we review our current knowledge on the role and the regulation of nim1 in connecting cell cycle and nutritional pathways.

Published
1995
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