Prohibitin and mitochondrial biology

8 pages, 2 figures.--PMID: 19733482 [PubMed]Prohibitins are ubiquitous, evolutionarily conserved proteins that are mainly localized in mitochondria. The mitochondrial prohibitin complex comprises two subunits, PHB1 and PHB2. These two proteins assemble into a ring-like macromolecular structure at the inner mitochondrial membrane and are implicated in diverse cellular processes: from mitochondrial biogenesis and function to cell death and replicative senescence. In humans, prohibitins have been associated with various types of cancer. While their biochemical function remains poorly understood, studies in organisms ranging from yeast to mammals have provided significant insights into the role of the prohibitin complex in mitochondrial biogenesis and metabolism. Here we review recent studies and discuss their implications for deciphering the function of prohibitins in mitochondriaThis work was supported by the European Commission Coordination Action ENINET (contract number LSHM-CT-2005-19063).Peer reviewe

Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans

Necrotic cell death is defined by distinctive morphological characteristics that are displayed by dying cells (Walker, N.I., B.V. Harmon, G.C. Gobe, and J.F. Kerr. 1988. Methods Achiev. Exp. Pathol. 13:18–54). The cellular events that transpire during necrosis to generate these necrotic traits are poorly understood. Recent studies in the nematode Caenorhabditis elegans show that cytoplasmic acidification develops during necrosis and is required for cell death (Syntichaki, P., C. Samara, and N. Tavernarakis. 2005. Curr. Biol. 15:1249–1254). However, the origin of cytoplasmic acidification remains elusive. We show that the alkalization of endosomal and lysosomal compartments ameliorates necrotic cell death triggered by diverse stimuli. In addition, mutations in genes that result in altered lysosomal biogenesis and function markedly affect neuronal necrosis. We used a genetically encoded fluorescent marker to follow lysosome fate during neurodegeneration in vivo. Strikingly, we found that lysosomes fuse and localize exclusively around a swollen nucleus. In the advanced stages of cell death, the nucleus condenses and migrates toward the periphery of the cell, whereas green fluorescent protein–labeled lysosomal membranes fade, indicating lysosomal rupture. Our findings demonstrate a prominent role for lysosomes in cellular destruction during necrotic cell death, which is likely conserved in metazoans

Prolonged quiescence delays somatic stem cell-like divisions in Caenorhabditis elegans and is controlled by insulin signaling

Cells can enter quiescence in adverse conditions and resume proliferation when the environment becomes favorable. Prolonged quiescence comes with a cost, reducing the subsequent speed and potential to return to proliferation. Here, we show that a similar process happens during Caenorhabditis elegans development, providing an in vivo model to study proliferative capacity after quiescence. Hatching under starvation provokes the arrest of blast cell divisions that normally take place during the first larval stage (L1). We have used a novel method to precisely quantify each stage of postembryonic development to analyze the consequences of prolonged L1 quiescence. We report that prolonged L1 quiescence delays the reactivation of blast cell divisions in C. elegans, leading to a delay in the initiation of postembryonic development. The transcription factor DAF‐16/FOXO is necessary for rapid recovery after extended arrest, and this effect is independent from its role as a suppressor of cell proliferation. Instead, the activation of DAF‐16 by decreased insulin signaling reduces the rate of L1 aging, increasing proliferative potential. We also show that yolk provisioning affects the proliferative potential after L1 arrest modulating the rate of L1 aging, providing a possible mechanistic link between insulin signaling and the maintenance of proliferative potential. Furthermore, variable yolk provisioning in embryos is one of the sources of interindividual variability in recovery after quiescence of genetically identical animals. Our results support the relevance of L1 arrest as an in vivo model to study stem cell‐like aging and the mechanisms for maintenance of proliferation potential after quiescence.Spanish Ministerio de Economía y Competitividad (BFU2016-74949-P and BFU2012- 35509)European Research Council (ERC-2011-StG-281691)Marie-Curie Intra-European Fellowship (FP7-PEOPLE-2013- IEF/GA Nr: 627263

Geometría Riemanniana en dimensión baja

Recoge resultados importantes del plano proyectivo complejo visto como espacio con una métrica riemanniana, mostrando maneras sencillas de medir distancias y consecuencias métricas muy interesantes. A su vez, realizamos un estudio exhaustivo de las cónicas lisas en el plano proyectivo complejo para finalmente caracterizarlas con la curvatura de Gauss, demostrando además que dos cónicas son homotéticas si y solo si son isométricas

Nuclear organization in stress and aging

This article belongs to the Special Issue Nuclear Organisation.The eukaryotic nucleus controls most cellular processes. It is isolated from the cytoplasm by the nuclear envelope, which plays a prominent role in the structural organization of the cell, including nucleocytoplasmic communication, chromatin positioning, and gene expression. Alterations in nuclear composition and function are eminently pronounced upon stress and during premature and physiological aging. These alterations are often accompanied by epigenetic changes in histone modifications. We review, here, the role of nuclear envelope proteins and histone modifiers in the 3-dimensional organization of the genome and the implications for gene expression. In particular, we focus on the nuclear lamins and the chromatin-associated protein BAF, which are linked to Hutchinson–Gilford and Nestor–Guillermo progeria syndromes, respectively. We also discuss alterations in nuclear organization and the epigenetic landscapes during normal aging and various stress conditions, ranging from yeast to humans.Work in the M.A.-S. and P.A. laboratories is funded by the Spanish Ministry of Science, Innovation and Universities (BFU2016-79313-P to P.A. & MDM-2016-0687 to P.A. and M.A.-S.), the European Research Council (ERC-2011-StG-281691 to M.A.-S.) and the European Regional Development Fund.Peer reviewe

Prohibitin-mediated lifespan and mitochondrial stress implicate SGK-1, insulin/IGF and mTORC2 in C. elegans

This is an open-access article distributed under the terms of the Creative Commons Attribution License.Lifespan regulation by mitochondrial proteins has been well described, however, the mechanism of this regulation is not fully understood. Amongst the mitochondrial proteins profoundly affecting ageing are prohibitins (PHB-1 and PHB-2). Paradoxically, in C. elegans prohibitin depletion shortens the lifespan of wild type animals while dramatically extending that of metabolically compromised animals, such as daf-2-insulin-receptor mutants. Here we show that amongst the three kinases known to act downstream of daf-2, only loss of function of sgk-1 recapitulates the ageing phenotype observed in daf-2 mutants upon prohibitin depletion. Interestingly, signalling through SGK-1 receives input from an additional pathway, parallel to DAF-2, for the prohibitin-mediated lifespan phenotype. We investigated the effect of prohibitin depletion on the mitochondrial unfolded protein response (UPRmt). Remarkably, the lifespan extension upon prohibitin elimination, of both daf-2 and sgk-1 mutants, is accompanied by suppression of the UPRmtinduced by lack of prohibitin. On the contrary, gain of function of SGK-1 results in further shortening of lifespan and a further increase of the UPRmtin prohibitin depleted animals. Moreover, SGK-1 interacts with RICT-1 for the regulation of the UPRmtin a parallel pathway to DAF-2. Interestingly, prohibitin depletion in rict-1 loss of function mutant animals also causes lifespan extension. Finally, we reveal an unprecedented role for mTORC2-SGK-1 in the regulation of mitochodrial homeostasis. Together, these results give further insight into the mechanism of lifespan regulation by mitochondrial function and reveal a cross-talk of mitochondria with two key pathways, Insulin/IGF and mTORC2, for the regulation of ageing and stress response.This work was funded by grants from the European Research Council (ERC-2011-StG-281691) and the Spanish Ministerio de Economía y Competitividad (BFU2012-35509) to M.A.S. The study was also supported by grants from the Deutsche Forschungsgemeinschaft DFG (SFB746, SFB850) to R.B. and from BIOSS Centre for Biological Signalling Studies to R.B and M.A.S.Peer Reviewe

Modelado general y simulación de sistemas de almacenamiento de energía híbridos

Este trabajo de Fin de Máster tiene como objetivo principal el análisis e implementación de un modelo energético para una instalación híbrida de almacenamiento de energía eléctrica. A su vez, el estudio y modelado de elementos de almacenamiento de energía (baterías en concreto) e implementación de diferentes políticas de control de la instalación híbrida y políticas de reemplazo de los elementos de almacenamiento de la instalación, son otros objetivos que se plantean en este trabajo.En primer lugar, llevamos a cabo la revisión bibliográfica sobre instalaciones híbridas de almacenamiento, desde las perspectivas de topologías de conexionado y arquitecturas de control. Además, se incluye una revisión sobre los elementos de almacenamiento, junto a sus propiedades físicas y métricas más representativas.Comprendida la fase de revisión bibliográfica, modelamos e implementamos un modelo en espacio de estado para una instalación híbrida con topología en bus común. A su vez, se implemente un modelo de batería, como elementos de almacenamiento, a nivel energético y también a nivel de envejecimiento y degradación.Finalizado los modelos de instalación y batería, se plantean e implementan dos políticas de carga, que seleccionan el elemento que va a trabajar en función del estado de salud de los elementos de almacenamiento que conforman la instalación híbrida. A su vez, se implementan dos políticas de reemplazo de los elementos en función de las políticas de carga utilizada.Para finalizar, a través de los resultados obtenidos entre las comparativas de las políticas de carga y reemplazo, e instalaciones convencionales de almacenamiento, en función de un conjunto de métricas planteadas, se concluye las ventajas que presentan las instalaciones híbridas frente a las convencionales y las políticas que son más factibles en uso.<br /

Combined flow cytometry and high-throughput image analysis for the study of essential genes in Caenorhabditis elegans

Background: Advances in automated image-based microscopy platforms coupled with high-throughput liquid workflows have facilitated the design of large-scale screens utilising multicellular model organisms such as Caenorhabditis elegans to identify genetic interactions, therapeutic drugs or disease modifiers. However, the analysis of essential genes has lagged behind because lethal or sterile mutations pose a bottleneck for high-throughput approaches, and a systematic way to analyse genetic interactions of essential genes in multicellular organisms has been lacking. Results: In C. elegans, non-conditional lethal mutations can be maintained in heterozygosity using chromosome balancers, commonly expressing green fluorescent protein (GFP) in the pharynx. However, gene expression or function is typically monitored by the use of fluorescent reporters marked with the same fluorophore, presenting a challenge to sort worm populations of interest, particularly at early larval stages. Here, we develop a sorting strategy capable of selecting homozygous mutants carrying a GFP stress reporter from GFP-balanced animals at the second larval stage. Because sorting is not completely error-free, we develop an automated high-throughput image analysis protocol that identifies and discards animals carrying the chromosome balancer. We demonstrate the experimental usefulness of combining sorting of homozygous lethal mutants and automated image analysis in a functional genomic RNA interference (RNAi) screen for genes that genetically interact with mitochondrial prohibitin (PHB). Lack of PHB results in embryonic lethality, while homozygous PHB deletion mutants develop into sterile adults due to maternal contribution and strongly induce the mitochondrial unfolded protein response (UPR mt ). In a chromosome-wide RNAi screen for C. elegans genes having human orthologues, we uncover both known and new PHB genetic interactors affecting the UPR mt and growth. Conclusions: The method presented here allows the study of balanced lethal mutations in a high-throughput manner. It can be easily adapted depending on the user's requirements and should serve as a useful resource for the C. elegans community for probing new biological aspects of essential nematode genes as well as the generation of more comprehensive genetic networks.European Research Council ERC-2011-StG-281691Ministerio de Economía y Competitividad BFU2012–3550

An automated method for the analysis of food intake behaviour in Caenorhabditis elegans

The study of mechanisms that govern feeding behaviour and its related disorders is a matter of global health interest. The roundworm Caenorhabditis elegans is becoming a model organism of choice to study these conserved pathways. C. elegans feeding depends on the contraction of the pharynx (pumping). Thanks to the worm transparency, pumping can be directly observed under a stereoscope. Therefore, C. elegans feeding has been historically investigated by counting pharyngeal pumping or by other indirect approaches. However, those methods are short-term, time-consuming and unsuitable for independent measurements of sizable numbers of individuals. Although some particular devices and long-term methods have been lately reported, they fail in the automated, scalable and/or continuous aspects. Here we present an automated bioluminescence-based method for the analysis and continuous monitoring of worm feeding in a multi-well format. We validate the method using genetic, environmental and pharmacological modulators of pharyngeal pumping. This flexible methodology allows studying food intake at specific time-points or during longer periods of time, in single worms or in populations at any developmental stage. Additionally, changes in feeding rates in response to differential metabolic status or external environmental cues can be monitored in real time, allowing accurate kinetic measurements.España MINECO BFU2012-3550