Peroxisomal fission is modulated by the mitochondrial Rho-GTPases, Miro1 and Miro2

Peroxisomes are essential for a number of cellular functions, including reactive oxygen species metabolism, fatty acid β-oxidation and lipid synthesis. To ensure optimal functionality, peroxisomal size, shape and number must be dynamically maintained; however, many aspects of how this is regulated remain poorly characterised. Here, we show that the localisation of Miro1 and Miro2-outer mitochondrial membrane proteins essential for mitochondrial trafficking-to peroxisomes is not required for basal peroxisomal distribution and long-range trafficking, but rather for the maintenance of peroxisomal size and morphology through peroxisomal fission. Mechanistically, this is achieved by Miro negatively regulating Drp1-dependent fission, a function that is shared with the mitochondria. We further find that the peroxisomal localisation of Miro is regulated by its first GTPase domain and is mediated by an interaction through its transmembrane domain with the peroxisomal-membrane protein chaperone, Pex19. Our work highlights a shared regulatory role of Miro in maintaining the morphology of both peroxisomes and mitochondria, supporting a crosstalk between peroxisomal and mitochondrial biology

Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling

It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca(2+). Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca(2+)-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca(2+) in astrocytic processes. Thus, the regulation of intracellular Ca(2+) signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca(2+) wave propagation, gliotransmission, and ultimately neuronal function

Formal Hecke algebras and algebraic oriented cohomology theories

In the present paper we generalize the construction of the nil Hecke ring of Kostant-Kumar to the context of an arbitrary algebraic oriented cohomology theory of Levine-Morel and Panin-Smirnov, e.g. to Chow groups, Grothendieck's K_0, connective K-theory, elliptic cohomology, and algebraic cobordism. The resulting object, which we call a formal (affine) Demazure algebra, is parameterized by a one-dimensional commutative formal group law and has the following important property: specialization to the additive and multiplicative periodic formal group laws yields completions of the nil Hecke and the 0-Hecke rings respectively. We also introduce a deformed version of the formal (affine) Demazure algebra, which we call a formal (affine) Hecke algebra. We show that the specialization of the formal (affine) Hecke algebra to the additive and multiplicative periodic formal group laws gives completions of the degenerate (affine) Hecke algebra and the usual (affine) Hecke algebra respectively. We show that all formal affine Demazure algebras (and all formal affine Hecke algebras) become isomorphic over certain coefficient rings, proving an analogue of a result of Lusztig.Comment: 28 pages. v2: Some results strengthened and references added. v3: Minor corrections, section numbering changed to match published version. v4: Sign errors in Proposition 6.8(d) corrected. This version incorporates an erratum to the published versio

Serological and Molecular Survey of Hepatitis E Virus in Small Ruminants from Central Portugal

Hepatitis E virus (HEV) is currently recognized as an emerging problem and a growing concern for public health in developed countries, with HEV infections mainly attributable to foodborne transmission of HEV-3. The zoonotic HEV genotype 3 infects a wide range of mammalian hosts, with swine considered as the primary host. This study investigates the occurrence of HEV among small ruminants in Portugal. The primary aim of the present research was to evaluate the circulation and the potential for HEV infection among sheep and goats. A total of 400 bile samples and 493 blood samples were collected from sheep and goats at a slaughterhouse in the center region of Portugal, between January 2022 and March 2023. The HEV RNA detection in bile samples was performed using a nested broad-spectrum RT-PCR targeting the ORF1 region. Serological analysis to detect anti-HEV antibodies was conducted using a commercial double-antigen sandwich multi-species ELISA. The HEV RNA was not detected in any bile samples using the nested broad-spectrum RT-PCR. Serological analysis revealed an overall HEV antibody seroprevalence of 2% (10/493, 95% CI: 0.98–3.70) among the small ruminants, namely 2.2% in goats and 2.0% in sheep. Curiously, no statistically significant association among the factors, age, sex and species and HEV seroprevalence was observed. Although HEV RNA was not detected in the bile of sheep and goats, this study the evidence of seroprevalence in these small ruminant species. Further research could provide additional insights into the factors influencing HEV transmission dynamics in small ruminants in Portugal and its potential implications for public health. © The Author(s) 2024."Sérgio Santos-Silva thanks Fundação para a Ciência e a Tecnologia (FCT) for the financial support of his Ph.D work under the scholarship 2021.09461.BD contract through the Maria de Sousa-2021 program. Helena M.R. Gonçalves received financial support from FCT/MCTES, DOI 10.54499/UIDP/50006/2020 and DOI 10.54499/2022.04199.CEECIND/CP1724/CT0008. António Rivero-Juarez is supported by a contract from the Spanish Junta de Andalucía (Nicolas Monardes program: C1-0001-2023). Pedro López-López was the recipient of a Margarita Salas contract funded by Plan de Recuperación, Transformación y Resiliencia, NextGeneration EU. Open access funding provided by FCT|FCCN (b-on). This research was funded by Fundação para Ciência e Tecnologia (FCT), grant number 2021.09461.BD.

Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response

Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1/Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease

Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality

DUDAS DE ENFERMERÍA EN EL MANEJO DE LA HISTORIA CLÍNICA. ASPECTOS JURÍDICOS

  As part of the changes produced within the nursing profession, the registration of the activities carried out proves to be necessary for the management of quality care, keeping in mind the legal aspect and development of nursing training. According to Spanish Act 41/2002, clinical history is the array of documents related to the care process of every patient, including the identification of doctors and health professionals that have intervened in the care. Its objective is to facilitate sanitary care, paying attention to aspects such as training and research, evaluation of the quality of care, administration and medical-legal.   The Spanish Act 41/2002 determines which documents are obligatory and should be present in the clinical history. Among these are the care planning sheets, the records of therapeutic work and vital signs. All these should be present in each one of the moments along with the correspondent identification of the people carrying out the action, as these imply legal responsibility, as long as law compliance is guaranteed. Therefore, nursing must understand and fulfill the regulation regarding the use of clinical history.   Nursing records are the documental tool where all the information of nursing activity is collected regarding a specific patient, assessment, received treatment, and progression. Nursing records are an essential part of the clinical history and therefore, have similar functions; the main one being treatment, focused on providing maximum quality care, as well as the researcher-trainer, management and contribution to the development of our profession. Other objectives are legal because the records are the documented testimony of the professional actions upon the Court requirements.  Dentro de los cambios producidos en la profesión enfermera, el registro de las actividades realizadas se revela como imprescindible para administrar unos cuidados de calidad, sin olvidar el punto de vista legal y el desarrollo de la formación en Enfermería. Según la Ley 41/2002, la Historia Clínica comprende el conjunto de documentos relativos a los procesos asistenciales de cada paciente, con la identificación de los médicos y los profesionales sanitarios que han intervenido en ellos, y tiene como fin principal facilitar la asistencia sanitaria, sin obviar aspectos como la docencia e investigación, la evaluación calidad asistencial, la administrativa y la médico-legal.La Ley 41/2002 determina los documentos obligatorios que deben estar presentes en la Historia clínica. Entre ellos se encuentran las hojas de planificación de los cuidados, el registro de las aplicaciones terapéuticas y el registro de las constantes. Todos ellos deben estar presentes en cada uno de los episodios con la correspondiente identificación de la persona que lo realiza, pues implica responsabilidad jurídica, en tanto en cuanto hay que garantizar el cumplimiento de la ley. Por ello enfermería debe conocer y cumplir lo legislado respecto al uso de la Historia clínica.Los registros de enfermería son el soporte documental donde queda recogida toda la información sobre la actividad enfermera referente a una persona concreta, valoración, tratamiento recibido y su evolución. Los Registros de Enfermería son parte fundamental de la Historia Clínica y como tal tienen funciones similares; la principal sería la asistencial, enfocada a prestar unos cuidados de la máxima calidad, sin olvidar la docente-investigadora, de gestión y la contribución al desarrollo de nuestraprofesión. Otras de sus finalidades es la jurídico-legal, pues los registros constituyen el testimonio documental de los actos del profesional a requerimiento de los tribunale

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ

Pleiotropic functions of the tumor- and metastasis-suppressing Matrix Metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity which has onco-suppressive actions in numerous tumor types

Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome

Adaptor protein (AP) complexes mediate key sorting decisions in the cell through selective incorporation of transmembrane proteins into vesicles. Little is known of the roles of AP-4, despite its loss of function leading to a severe early onset neurological disorder, AP-4 deficiency syndrome. Here we demonstrate an AP-4 epsilon subunit knockout mouse model that recapitulates characteristic neuroanatomical phenotypes of AP-4 deficiency patients. We show that ATG9A, critical for autophagosome biogenesis, is an AP-4 cargo, which is retained within the trans-Golgi network (TGN) in vivo and in culture when AP-4 function is lost. TGN retention results in depletion of axonal ATG9A, leading to defective autophagosome generation and aberrant expansions of the distal axon. The reduction in the capacity to generate axonal autophagosomes leads to defective axonal extension and de novo generation of distal axonal swellings containing accumulated ER, underlying the impaired axonal integrity in AP-4 deficiency syndrome