Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT

Mutations in the MFN2 gene are associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a dominant axonal CMT, whereas mutations in GDAP1 are associated with recessive demyelinating CMT (CMT4A), recessive axonal CMT (AR-CMT2), and dominant axonal CMT (CMT2K). Both proteins are involved in energy metabolism and dynamics of the mitochondrial network. We have previously reported that, in fibroblasts from patients with CMT, MFN2 mutations resulted in a mitochondrial energy coupling defect, whereas dominant mutation in GDAP1 resulted in defective complex I activity. In this study, we investigated mitochondrial bioenergetics from a severely affected patient with CMT harboring combined mutations in both GDAP1 and MFN2 genes

Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect

PurposeAutosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to retinal ganglion cell degeneration and reduced visual acuity during the early decades of life, is mainly associated with mutations in the OPA1 gene. Here we report a novel ADOA phenotype associated with a new pathogenic OPA1 gene mutation. Methods The patient, a 62-year-old woman, was referred for acute, painless, and severe visual loss in her right eye. Acute visual loss in her left eye occurred a year after initial presentation. MRI confirmed the diagnosis of isolated atrophic bilateral optic neuropathy. We performed DNA sequencing of the entire coding sequence and the exon/intron junctions of the OPA1 gene, and we searched for the mitochondrial DNA mutations responsible for Leber hereditary optic atrophy by sequencing entirely mitochondrial DNA. Mitochondrial respiratory chain complex activity and mitochondrial morphology were investigated in skin fibroblasts from the patient and controls. Results We identified a novel heterozygous missense mutation (c.2794C>T) in exon 27 of the OPA1 gene, resulting in an amino acid change (p.R932C) in the protein. This mutation, which affects a highly conserved amino acids, has not been previously reported, and was absent in 400 control chromosomes. Mitochondrial DNA sequence analysis did not reveal any mutation associated with Leber hereditary optic neuropathy or any pathogenic mutations. The investigation of skin fibroblasts from the patient revealed a coupling defect of oxidative phosphorylation and a larger proportion of short mitochondria than in controls. Conclusions The presence of an OPA1 mutation indicates that this sporadic, late-onset acute case of optic neuropathy is related to ADOA and to a mitochondrial energetic defect. This suggests that the mutational screening of the OPA1 gene would be justified in atypical cases of optic nerve atrophy with no evident cause

Structural insights into chaperone addiction of toxin-antitoxin systems

International audienceSecB chaperones assist protein export by binding both unfolded proteins and the SecA motor. Certain SecB homologs can also control toxin-antitoxin (TA) systems known to modulate bacterial growth in response to stress. In such TA-chaperone (TAC) systems, SecB assists the folding and prevents degradation of the antitoxin, thus facilitating toxin inhibition. Chaperone dependency is conferred by a C-terminal extension in the antitoxin known as chaperone addiction (ChAD) sequence, which makes the antitoxin aggregation-prone and prevents toxin inhibition. Using TAC of Mycobacterium tuberculosis, we present the structure of a SecB-like chaperone bound to its ChAD peptide. We find differences in the binding interfaces when compared to SecB–SecA or SecB-preprotein complexes, and show that the antitoxin can reach a functional form while bound to the chaperone. This work reveals how chaperones can use discrete surface binding regions to accommodate different clients or partners and thereby expand their substrate repertoire and functions

Métabolisme énergétique mitochondrial dans les neuropathies héréditaires associées aux mutations des gènes OPA1 et MFN2

Autosomal dominant optic atrophy (ADOA) and Charcot-Marie-Tooth type 2A disease are two hereditary neuropathies associated with mutations in OPA1 and MFN2 genes respectively. These genes encode OPA1 and MFN2 proteins involved in mitochondrial fusion. Mitochondria being essential organelles for ATP production, we hypothesised that a mitochondrial energetic defect could take part in ADOA and CMT2A pathogenesis. We showed a decrease in oxidative phosphorylation efficiency in skin fibroblasts from patients affected by ADOA and CMT2A. This uncoupling was associated with a decrease in complex IV activity and an increase in complex V activity in ADOA fibroblasts. In CMT2A fibroblasts, the uncoupling was associated with increased adenine nucleotide translocase (ANT) activity and expression. Study of brain mitochondria from a MFN2(R94Q) mouse model of CMT2A showed mitochondrial complexes II and V deficiencies associated with ATP-sensitive potassium channels opening. These results demonstrated that OPA1 and MFN2 proteins involved in mitochondrial dynamics play a major role in mitochondrial energetic metabolism.L'atrophie optique autosomique dominante (ADOA) et la maladie de Charcot-Marie-Tooth de type 2A (CMT2A) sont deux neuropathies héréditaires respectivement liées aux mutations des gènes OPA1 et MFN2. Les protéines OPA1 et MFN2 sont impliquées dans la dynamique de fusion des mitochondries. Ces organites intracellulaires sont essentiels dans les processus de synthèse d'ATP. L'hypothèse d'un déficit énergétique impliqué dans la physiopathologie de ces neuropathies devait alors être testée. Nous avons mis en évidence une baisse d'efficacité des phosphorylations oxydatives dans les fibroblastes de peau de patients atteints d'ADOA et de CMT2A. Ce découplage est associé à une baisse d'activité du complexe IV et à une augmentation de l'activité du complexe V dans le cas de l'ADOA. Dans le cas de la CMT2A, le découplage est associé à une augmentation de l'activité et de la quantité de la translocase des nucléotides adényliques (ANT). Une étude sur mitochondries isolées de cerveaux d'un modèle murin MFN2(R94Q) de CMT2A montre une baisse d'activité des complexes II et V associée à l'ouverture du canal mitochondrial potassique sensible à l'ATP (mKATP). Nos résultats montrent qu'OPA1 et MFN2, deux protéines de la dynamique mitochondriale ont un rôle majeur dans la régulation énergétique mitochondriale

Colloque. La coexistence confessionnelle en France et dans les mondes germaniques

Du 18 au 20 octobre 2012, se tiendra à Strasbourg un colloque international portant sur La coexistence confessionnelle en France et dans les mondes germaniques du Moyen Âge à nos jours. Il est organisé par la Société d’histoire religieuse de la France, l’université de Strasbourg (EA ARCHE) et l’Institut universitaire de France. Programme : Jeudi 18 octobre / Après-midi Présidence de séance : Jean-Marie Husser, université de Strasbourg. 14h00 : Ouverture du colloque. Nicolas Bourguinat, direct..

A three wave design: reciprocal relationships between motivation and basic psychological needs

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Understanding parent stressors and coping experiences in elite sports contexts.

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Groupe de travail « Philosophie des mathématiques »

Responsables : Giuseppina Ronzitti et Tero Tulenheimo 1ère séance : vendredi 28 septembre 2012, 13h-15h Introduction du séminaire de lecture de Pénélope Maddy, Realism in mathematics - Clarendon Press, 1992, par G. Ronzitti. voir le site du groupe de travail. Université Lille 3, Maison de la recherche, salle F1.07