Inhibition of the Mitochondrial Permeability Transition for Cytoprotection: Direct versus Indirect Mechanisms

Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acid β oxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies

Feeling better:Tactile verbs speed up tactile detection

International audienceEmbodiment of action-related language into the motor system has been extensively documented. Yet the case of sensory words, especially referring to touch, remains overlooked. We investigated the influence of verbs denoting tactile sensations on tactile perception. In Experiment 1, participants detected tactile stimulations on their forearm, preceded by tactile or non-tactile verbs by one of three delays (170, 350, 500ms) reflecting different word processing stages. Results revealed shorter reaction times to tactile stimulations following tactile than non-tactile verbs, irrespective of delay. To ensure that priming pertained to tactile, and not motor, verb properties, Experiment 2 compared the impact of tactile verbs to both action and non-tactile verbs, while stimulations were delivered on the index finger. No priming emerged following action verbs, therefore not supporting the motor-grounded interpretation. Facilitation by tactile verbs was however not observed, possibly owing to methodological changes. Experiment 3, identical to Experiment 2 except that stimulation was delivered to participants’ forearm, replicated the priming effect. Importantly, tactile stimulations were detected faster after tactile than after both non-tactile and action verbs, indicating that verbs’ tactile properties engaged resources shared with sensory perception. Our findings suggest that language conveying tactile information can activate somatosensory representations and subsequently promote tactile detection

Mitochondrial Roles and Cytoprotection in Chronic Liver Injury

The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts

Molecular and functional characterization of a new X-linked chronic granulomatous disease variant (X91+) case with a double missense mutation in the cytosolic gp91phox C-terminal tail

AbstractWe report here two atypical cases of X-linked CGD patients (first cousins) in which cytochrome b558 is present at a normal level but is not functional (X91+). The mutations were localized by single-strand conformational polymorphism of reverse transcriptase–polymerase chain reaction amplified fragments and then identified by sequence analysis. They consisted in two base substitutions (C919 to A and C923 to G), changing His303 to Asn and Pro304 to Arg in the cytosolic gp91phox C-terminal tail. Mismatched polymerase chain reaction and genomic DNA sequencing showed that mothers had both wild-type and mutated alleles, confirming that this case was transmitted in an X-linked fashion. A normal amount of FAD was found in neutrophil membranes, both in the X91+ patients and their parents. Epstein–Barr virus-transformed B lymphocytes from the X91+ patients acidified normally upon stimulation with arachidonic acid, indicating that the mutated gp91phox still functioned as a proton channel. A cell-free translocation assay demonstrated that the association of the cytosolic factors p47phox and p67phox with the membrane fraction was strongly disrupted. We concluded that residues 303 and 304 are crucial for the stable assembly of the NADPH oxidase complex and for electron transfer, but not for its proton channel activity

Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion

During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH + I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH + I/R. © 2010 Macmillan Publishers Limited.This work was supported by the Ministerio de Educación y Ciencia (project grant SAF 2005-00385; project grant manager BFU2009-07410) (Madrid, Spain) and the Ministerio de Sanidad y Consumo (project grant PIO60021) (Madrid, Spain). Centro de Investigaciones Biomédicas Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is supported by the Instituto de Salud Carlos III (Spain).Peer Reviewe

A novel point mutation in the CYBB gene promoter leading to a rare X minus chronic granulomatous disease variant — Impact on the microbicidal activity of neutrophils

AbstractThis article reports an atypical and extremely rare case of X-linked CGD in an Italian family characterized by a low expression of gp91phox (X91− CGD). A novel point mutation in the CYBB gene's promoter (insertion of a T at position −54T to −56T) appeared to prevent the full expression of this gene in the patient's neutrophils and correlated with a residual oxidase activity in the whole cells population. The expression and functional activity of the oxidase in eosinophils appeared to be almost normal. Gel shift assays indicated that the mutation led to decreased interactions with DNA-binding proteins. The total O2− production in the patient's granulocytes (5–7% of normal) supported no microbicidal power after 45 min and 60 min of contact with S. aureus and C. albicans, respectively. Despite this residual oxidase activity, the patients suffered from severe and life-threatening infections. It was concluded that in these X91− CGD neutrophils, the O2− production per se was not sufficient to protect the patient against severe infections

Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis

La stéatose hépatique non-alcoolique consiste en une accumulation de lipides dans le cytoplasme des hépatocytes. Longtemps considérée comme une pathologie bénigne, elle peut être à l’origine du développement d’un stade plus sévère : la stéatohépatite non alcoolique (NASH). La NASH s’accompagne de lésions sévères du foie liées à la genèse d’un stress oxydant, d’une inflammation et de la mort cellulaire. Le rôle de la mitochondrie est au centre de cette maladie, bien que les connaissances sur la dysfonction mitochondriale et ses conséquences sur l’apoptose soient encore insuffisantes. En effet, la mitochondrie est responsable de la dégradation des lipides par -oxydation et elle agit comme un centre intégrateur des signaux apoptotiques en déclenchant une perméabilisation des membranes mitochondriales (PMM) aboutissant à la libération de facteurs apoptogènes. Ce processus est considéré comme le point de non-retour de la voie mitochondriale de l’apoptose. Nos travaux ont porté sur la compréhension des mécanismes moléculaires liant l’apoptose hépatocytaire mitochondriale et la stéatose. La combinaison de quatre modèles expérimentaux de stéatose (biopsies de patients, mitochondries isolées de souris obèses ob/ob ou recevant un régime hypercalorique, et lignées cellulaires) a permis de montrer, dans le foie stéatosique, une sensibilité accrue à l’induction de la PMM et une augmentation de la perméabilité de VDAC (voltage-dependent anion channel), protéine formant un canal dans la membrane externe mitochondriale. Ces observations sont associées à une diminution de la phosphorylation de VDAC sur un résidu thréonine et sa perte d’interaction avec la protéine anti-apoptotique Bcl-XL et la kinase GSK3, révélant ainsi une nouvelle voie de signalisation par les lipides. Cette découverte s’est notamment appuyée sur l’utilisation de tests fonctionnels en mitochondries isolées que nous avions développés et validés dans plusieurs études aux stratégies expérimentales variées. En conclusion, notre étude permet de mieux comprendre la fragilité mitochondriale lipo-induite, stade précédant l’apoptose hépatocytaire, et ouvre des perspectives à visée biomédicale.Non-alcoholic steatosis is a liver disease characterized by lipid accumulation in the cytoplasm of hepatocytes. For a long time, it has been considered as a benign condition. Now it is known that it can precede the development of a severe stage, non-alcoholic steatohepatitis (NASH). NASH is accompanied by severe dammages of the liver linked to the genesis of oxidative stress, inflammation and cell death. Mitochondrion is a central player of this disease; however, the knowledge of mitochondrial dysfunction and its consequences on apoptosis is still insufficient. Indeed, mitochondria are responsible for lipid degradation by -oxidation. Mitochondria act as a central integrator of apoptotic signals by triggering the mitochondrial membrane permeabilization (MMP) leading to the release of apoptogenic factors. This process is considered as the point of no return of the mitochondrial pathway of apoptosis. We aimed to better understand the molecular mechanisms linking mitochondrial liver apoptosis and steatosis. Combination of four experimental models of steatosis (human biopsies, isolated mitochondria from ob/ob obese mice, high fat diet-fed mice or hepatic cell lines) displayed, in steatotic livers, increased sensitivity to MMP induction and permeability of VDAC (Voltage dependent anion channel), a protein which forms a channel in the outer mitochondrial membrane. These findings are associated with the hypo-phosphorylation of VDAC on a threonine residue and the loss of its interaction with the anti-apoptotic Bcl-XL and GSK3 kinase, thus revealing a new lipid-induced signaling pathway. Our work is based on the use of functional assays on isolated mitochondria that we have developed and validated in several studies involving various strategies. To conclude, our study increases the knowledge on the lipid-induced mitochondrial weakness preceding hepatic apoptosis and opens perspectives in biomedical application

Paludisme d'importation des Comores à Marseille (période 2001 à 2011)

INTRODUCTION: à Marseille, où vivent près de 80 000 personnes originaires des Comores, plus de 80% des cas de paludisme ont été contractés aux Comores. Ceci s'explique par le flux migratoire intense entre Marseille et cet archipel, qui crée un véritable couloir de connaissances entre ces deux régions. OBJECTIFS: étudier les aspects épidémiologiques, cliniques et thérapeutiques du paludisme importé des Comores à Marseille, ainsi que leurs tendances évolutives sur 11 ans, afin de mettre en évidence une éventuelle transition générationnelle. MATERIEL ET METHODES: étude rétrospective, incluant tous les cas de paludisme importé des Comores traités dans les 4 hôpitaux publics de Marseille, entre le 01 janvier 2001 et le 31 décembre 2011. RESULTATS: 64,9% des cas étaient importés des Comores soit 1437 patients inclus dans l'étude (928 adultes et 509 enfants). Une chimioprophylaxie a été suivie par 45,3% des adultes contre 79,1% des enfants (p<0,001). Dans 87,3% des cas, elle n'était pas adaptée. Plasmodium falciparum était responsable de 83,2% des cas. Parmi les 147 accès graves, aucun décès n'a été observé. Le paludisme d'importation des Comores à Marseille est responsable de 4772 jours d'hospitalisation en 11 ans. Sur les 11 années d'étude, le nombre de cas de paludisme a diminué, particulièrement en 2011 avec une baisse de 83,3% du paludisme importé des Comores par rapport à 2010 alors que le paludisme importé des autres pays est resté stable. La 2e génération de migrants a plus souvent pris une chimioprophylaxie et a un délai de recours aux soins plus court (2 jours contre 3 jours, p=0,01). Malgré une parasitémie plus élevée, la fréquence des formes sévères y est plus faible par rapport à la 1ere génération (p=0,02). DISCUSSION: Les nombre de cas de paludisme importé des Comores a chuté de façon brutale en 2011, résultat d'une stratégie mise en place en 2010 aux Comores, associant distribution de moustiquaires imprégnées et d'insecticides de masse, tests de diagnostic rapide et traitement gratuit par artémétherluméfantrine. Le nombre d'accès gaves a diminué au cours de l'étude et ont été moins fréquents chez les enfants et les adultes jeunes de la 2e génération. Aucun paludisme grave n'a été traité par astérsunate qui n'est disponible en France que depuis 2011. CONCLUSION: Malgré son statu non immun, la 2e génération et les suivantes ne sont pas plus de formes graves, signe d'une prise de conscience de la nécessite de se protéger et d'une meilleure intégration dans le système de soins. Le nombre de cas de paludisme importé des Comores à Marseille diminue régulièrement, avec une cassure en 2011, probable fruit des politiques de lutte locale.INTRODUCTION: Some 80 000 Comorians people are living in Marseille and 80% fo malaria cases diagnosed in Marseille are imported from Comoros. It reflects the important human flow between this two geographical area, generating a real channel of knowledge on Comoros-acquired malaria. OBJECTIVES OF THE STUDY: Study epdidemiological, clinical, therapeutic characteristics of Comoros-acquiered malaria in Marseille, to analyze the 11 year evolution trends and to investigate a possible transition between generation in the Comorian population in regards to malaria. PATIENTS AND METHODOLOGY: retrospectie study, includinf all patients treasted for Comoros-acquiered malaria and admitted in one of the 4 public hospitals in Marseille, between January 1st, 2001 and December, 31th 2011. RESULTS: a total of 1437 patients were included during the study period (928 adults and 509 children, median age: 30 years, sex ratio: 1,33) and represented 64,9% of all of the malaria cases. The most frequent specie was P. falciparum (83,2%) and 147 severe malaria were described with non death. Only 25,9% have taken vector measures and 45,3% of the results have taken chemoprophylaxis, vs 79,1% of the children (p<0,001). It was inappropriate in 87,3% of cases. Half of population had seen a medical practitioner before hospital. The number of Comoros-acquired malaria managed in Marseille's hospitals progressively decreased over the studied period with a dramatic fall in 2011, bith in adults (n=11) and children (n=7), while the annual incidence of malaria imported from the other countries remained rather stable. DISCUSSION: the incidence of imported malaria from Comoros in Marseille had dramatically decreased in 2011. this may result from the significant fall of malaria transmission in the visited island, thanks to control vector diffusion, use of insecticide-treated mosquito nets, early diagnosis by rapid antigenic tests and free use of artemisin combined therapy. This hypothesis is confirmed by the local data. Chrildren and young adults, descendants of migrants, had a higher parasite density because of a lower immunity, but delared less severe malaria, because of a bette information and understanding of the prevention measures. CONCLUSION: despite their non immune condition, people of the 2nd generation and the folowers did not developed more severe malaria, possibly thanks to better understanding of precention measures. The recent strong reduction of malaria cases, imported from Comoros archipelago in Marseille in 2011 is a positive event, probably explained by local control measures.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-Bib. Serv.Santé Armées (751055204) / SudocSudocFranceF