Spatio-Temporal Dynamics of Yeast Mitochondrial Biogenesis: Transcriptional and Post-Transcriptional mRNA Oscillatory Modules

Examples of metabolic rhythms have recently emerged from studies of budding yeast. High density microarray analyses have produced a remarkably detailed picture of cycling gene expression that could be clustered according to metabolic functions. We developed a model-based approach for the decomposition of expression to analyze these data and to identify functional modules which, expressed sequentially and periodically, contribute to the complex and intricate mitochondrial architecture. This approach revealed that mitochondrial spatio-temporal modules are expressed during periodic spikes and specific cellular localizations, which cover the entire oscillatory period. For instance, assembly factors (32 genes) and translation regulators (47 genes) are expressed earlier than the components of the amino-acid synthesis pathways (31 genes). In addition, we could correlate the expression modules identified with particular post-transcriptional properties. Thus, mRNAs of modules expressed “early” are mostly translated in the vicinity of mitochondria under the control of the Puf3p mRNA-binding protein. This last spatio-temporal module concerns mostly mRNAs coding for basic elements of mitochondrial construction: assembly and regulatory factors. Prediction that unknown genes from this module code for important elements of mitochondrial biogenesis is supported by experimental evidence. More generally, these observations underscore the importance of post-transcriptional processes in mitochondrial biogenesis, highlighting close connections between nuclear transcription and cytoplasmic site-specific translation

Yeast Mitochondrial Biogenesis: A Role for the PUF RNA-Binding Protein Puf3p in mRNA Localization

The asymmetric localization of mRNA plays an important role in coordinating posttranscriptional events in eukaryotic cells. We investigated the peripheral mitochondrial localization of nuclear-encoded mRNAs (MLR) in various conditions in which the mRNA binding protein context and the translation efficiency were altered. We identified Puf3p, a Pumilio family RNA-binding protein, as the first trans-acting factor controlling the MLR phenomenon. This allowed the characterization of two classes of genes whose mRNAs are translated to the vicinity of mitochondria. Class I mRNAs (256 genes) have a Puf3p binding motif in their 3'UTR region and many of them have their MLR properties deeply affected by PUF3 deletion. Conversely, mutations in the Puf3p binding motif alter the mitochondrial localization of BCS1 mRNA. Class II mRNAs (224 genes) have no Puf3p binding site and their asymmetric localization is not affected by the absence of PUF3. In agreement with a co-translational import process, we observed that the presence of puromycin loosens the interactions between most of the MLR-mRNAs and mitochondria. Unexpectedly, cycloheximide, supposed to solidify translational complexes, turned out to destabilize a class of mRNA-mitochondria interactions. Classes I and II mRNAs, which are therefore transported to the mitochondria through different pathways, correlated with different functional modules. Indeed, Class I genes code principally for the assembly factors of respiratory chain complexes and the mitochondrial translation machinery (ribosomes and translation regulators). Class II genes encode proteins of the respiratory chain or proteins involved in metabolic pathways. Thus, MLR, which is intimately linked to translation control, and the activity of mRNA-binding proteins like Puf3p, may provide the conditions for a fine spatiotemporal control of mitochondrial protein import and mitochondrial protein complex assembly. This work therefore provides new openings for the global study of mitochondria biogenesis

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Suivi qualitatif de l’évolution de 120 enfants porteurs de troubles du spectre autistique pris en charge par la méthode des 3i

International audienceAimThe 3i intervention is a developmental play-therapy method that considers that children with Autism Spectrum disorders (ASD) present an altered developmental process. It aims to help the child progress along a natural developmental path. Each developmental deficit is dealt with successively, with full attention to the specific sensory characteristics of each child. The method is based on Intensive Individual Interaction (the 3Is) of the child with adults. The 3i intervention is managed by the parents and selected care-givers, 5 to 6 hours per day, 7 days per week, to favor constant stimulation of the child. A key characteristic of the 3i method is the intervention of numerous selected care-givers, each contributing their preferred way of playing with the child and their enthusiasm. These selected care-givers are mostly non-professionals in the field of ASD. They undergo preliminary screening and receive initial training before interacting with the child in the playroom. They subsequently participate each month in a group session with the other participants, together with the parents, under the supervision of a trained psychologist.GoalThe main objective of this retrospective study was to assess the development of communication and social skills among children diagnosed with autism spectrum disorders (ASD), treated with the 3i method for 2 years.Methods120 subjects who pursued the 3i method for 24 months were included in this study, on the basis of their individual files kept by the psychologist, who conducted the monthly meeting with professionals during the implementation of the 3i method. The psychologist rated six indicators (Imitation, Gaze Quality, Social and Emotional Regulation, Verbal Expression, Non-Verbal Expression and Verbal Comprehension) from 1 to 3 (1: not acquired; 2: partially acquired and 3: competence acquired). Thus a developmental acquisition stage or score was allocated to each patient at the beginning of 3i Method and 24 months later.ResultsFor each indicator, the statistical analysis showed that the group of patients significantly increased their skills over the 24 months of the 3i method. On average, the patients reached a higher level of skills in four of the six skill areas. There was a relatively greater increase in the skills relating to imitation and non-verbal communication.DiscussionBeyond the limitations arising from the retrospective nature of the study, which used a non-standardized assessment scale, these results are consistent with a previous prospective study on 20 subjects using international standardized instruments. These results suggest that disabilities related to autism spectrum disorders decrease as a result of a 3i intervention, enabling better daily-life interaction with parents and as a second step better integration in school with peers.ConclusionThis method could reduce the intensity of the autistic syndrome and improve the ability of ASD children to interact with their environment.ObjectifL’objectif de cette étude rétrospective est de décrire l’évolution des compétences en communication et relation d’un groupe d’enfants porteurs de trouble du spectre autistique et traités par la méthode des 3i pendant 2 ans.MéthodeCent-vingt dossiers d’enfants ayant poursuivi cette méthode pendant 24 mois ont été inclus dans cette étude. Un score de 1 à 3 dans une échelle d’acquisition de compétences (1 : non acquise, 2 : partiellement acquise, 3 : acquise) a été attribué à chaque sujet pour chacun des six indicateurs choisis (Imitation, Qualité du regard, Régulation sociale et émotionnelle, Expression verbale, Expression non verbale et Compréhension verbale). Les scores initiaux sont comparés aux scores finaux après 24 mois de méthode 3i.RésultatsL’analyse statistique montre que pour chaque indicateur le groupe de patients a significativement progressé au cours des 24 mois de méthode 3i. En moyenne, les sujets acquièrent un stade supérieur dans 4 domaines de compétences sur 6. La progression est plus grande dans les domaines de l’imitation et de la communication non verbale.DiscussionMalgré les limites liées au caractère rétrospectif de l’étude et à une grille d’évaluation non standardisée, les résultats sont cohérents avec une précédente étude prospective sur 20 sujets avec des outils internationaux. Ce résultat suggère que les handicaps liés aux troubles du spectre autistique diminuent au cours de la prise en charge 3i.ConclusionCelle-ci pourrait permettre de réduire l’intensité du syndrome autistique et d’améliorer les capacités d’interaction avec l’environnement

Contribution à l'étude de l'assemblage des complexes respiratoires chez Saccharomyces cerevisiae

The biognesis of the respiratory complexes in mitochondria is an intricate process that need the Oxa1p function. In S. cerevisiae, the introduction of residu baring a positive charge in the transmembrane domain of two subunits of complex III : cytochrome c1 and Qcr9p, is able to compensate for the complex IV misassembly, due to the absence of the protein Oxa1p. The study of the mechanism of suppression suggest interaction between these positive charges and negative ones localised in the transmembrane domain of subunit of complex IV, allowing their insertion in the membrane. Oxa1p could allow the insertion of charged transmembrane domain in the mitochondrial inner membrane. The study of the suppressor mutations in presence of Oxa1p also shows interactions between subunits of complexes III and IV. Altogether these results suggest the presence of a supercomplexe III+IV and that the subunits of these complexes could interact before their insertion in the membraneVERSAILLES-BU Sciences et IUT (786462101) / SudocSudocFranceF

Physiological correction of lingual dysfunction with the “Tongue Right Positioner”: Beneficial effects on the upper airways

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Étude du confort et de l’efficacité du TRP dans le traitement du ronflement (résultats préliminaires)

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Microbiota–mitochondria inter-talk: consequence for microbiota–host interaction

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Clinical outcomes of interactive, intensive and individual (3i) play therapy for children with ASD: a two-year follow-up study

Abstract Background The outcomes of psycho-educational interventions for Autism Spectrum Disorders (ASDs) comorbid with severe to moderate intellectual disability (ID) are insufficiently documented. In this prospective study, we examined a developmental individual, interactive and intensive approach, called the ‘3i method’, which is based on play therapy. Methods Twenty DSM-IV-TR ASD subjects (mean chronological age 63.8 ± 37.8 months; mean developmental age 19.5 ± 6.6 months) were included and followed the 3i method for 24 months. Developmental and behavioural skills were assessed at baseline and after 24 months using the VABS, PEP-R and Nadel Imitation scale. Autism severity was evaluated using the Child Autism Rating Scale (CARS) and the Autism Diagnostic Interview (ADI-R). Results After 2 years of the 3i method, our 3 primary outcome variables significantly increased (VABS developmental age of socialization increased by 83%, age of communication by 34%, and Nadel Imitation score by 53%). Almost all VABS and PEP-R domains significantly improved. Additionally, increases in the VABS socialization score were positively correlated with the total number of treatment hours and CARS score; all ADI-R areas significantly decreased; and diagnoses had changed in 47.5% of the subjects (37% for PDD-NOS and even 10.5% for ID without PDD). Conclusion Children who followed the 3i method for 2 years had significantly improved behavioural and developmental skills and showed a clear decrease in autism severity. These results suggest that the 3i method may be useful for autistic children by improving their daily interactions with their social environment. Trial registration was retrospectively registered on May 20th, 2014 by the French Agency for drug and health (ANSM) under number ID-RCB 2014-A00542–45, reference: B148558–31

A transcriptome screen in yeast identifies a novel assembly factor for the mitochondrial complex III

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