Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling

All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism

Caracterización del Banco de La Concepción

Se integra información hidrográfica, geomorfológica, sedimentológica, biológica, sobre hábitats marinos y pesquera, para establecer las bases ecológicas necesarias para la protección y conservación del Banco de La ConcepciónEl proyecto INDEMARES ha permitido utilizar amplios medios económicos y personales para estudiar en detalle y desde múltiples perspectivas la zona del Banco de La Concepción. Se han aplicado metodologías para el estudio de la hidrografía, caracterizando la región, describiendo sus principales masas de agua y la hidrodinámica de las corrientes. También se ha abordado la geología de la zona, incluyendo levantamientos batimétricos, perfiles sísmicos, muestreos de sedimento y petrológicos, obteniendo modelos digitales del terreno, mapas de tipos de fondo, geomorfológicos. Se han caracterizado las comunidades bentopelágicas, demersales, epibentónicas y endobentónicas, prestando especial atención a aquellas que conforman o estructuran los hábitats sensibles cuyo inventariado y cartografía era objeto principal del proyecto. Los trabajos de identificación de hábitats se han realizado con muestreadores directos, pero también con muestreadores visuales, que han permitido hacer un mayor esfuerzo de muestreo sin aumentar el impacto sobre los fondos de la zona. Por otro lado se ha estudiado la huella pesquera de la zona por medio del análisis de los datos VMS y los cuadernos de pesca proporcionados por la SGP, además de una ardua labor a pie de puerto de entrevistas y encuestas. Toda la información ha sido gestionada y analizada por diferentes grupos de investigación de diferentes centros (Universidad de La Laguna, Instituto Universitario de Ciencias Políticas y Sociales, Universidad de Las Palmas de Gran Canaria, Instituto de Ciencias del Mar de Barcelona, Universidad de Barcelona, Centro de Investigaciones Medioambientales del Atlántico, Centro Oceanográfico de Santander y Centro Oceanográfico de Málaga del Instituto Español de Oceanografía, …), aunque el grueso de esta labor, además de la coordinación, se ha llevado a cabo en el Centro Oceanográfico de Canarias del Instituto Español de Oceanografía. Los resultados permiten tener un conocimiento profundo y multidisciplinar de la zona de estudio comparable a pocos proyectos de investigación marina en la macaronesia. El estudio oceanográfico, el geológico, y el de las comunidades biológicas, ha permitido la caracterización de los hábitats de la zona, y su cartografiado mediante el intenso muestreo y la aplicación de análisis de idoneidad de hábitats.INDEMARES Project made possible to bring together economic and staff resources to study in detail, and from multiple perspectives, the area of Banco de La Concepción. Methodologies have been applied to study hydrography, making a regional characterization, depicting main water masses, and current hydrodynamics. Geology has been tackled including bathymetric uplifting, seismic profiles, sediment and petrological sampling, obtaining digital terrain models, type of bottom maps, geomorphological maps, as an output. Benthopelagic, demersal, epibenthic and endobenthic communities have been characterized, paying special attention to sensitive habitats which inventory and mapping was the project’s main aim. Habitat identification has been made with direct and visual samplers, the latter making a major sampling effort possible without an increase of bottom impact. Moreover, fisheries footprint has been identified by Vessel Monitoring System data, together with logbooks from Secretaría General de Pesca (Fisheries Ministry), as well as a hard interviewing and surveying task at landing points. Information has been managed and analysed by different research groups from different Centres (Universidad de La Laguna, Instituto Universitario de Ciencias Políticas y Sociales, Universidad de Las Palmas de Gran Canaria, Instituto de Ciencias del Mar de Barcelona, Universidad de Barcelona, Centro de Investigaciones Medioambientales del Atlántico, Centro Oceanográfico de Santander y Centro Oceanográfico de Málaga del Instituto Español de Oceanografía), although the main body of the work, plus coordination, has been made by the Canary Islands Oceanographic Centre, from the Spanish Institute of Oceanography. Results let us have a multidisciplinary profound knowledge of the study zone, comparable to few other marine research projects off Macaronesia. The study about oceanography, geology and biologic communities has allowed the habitats characterization and mapping by means of intensive sampling and habitat suitability analysis.Instituto Español de Oceanografía, Comisión Europea Programa LIFE+, Fundación Biodiversida

Caracterización del Sur de Fuerteventura

Se integra información hidrográfica, geomorfológica, sedimentológica, biológica, sobre hábitats marinos y pesquera, para establecer las bases ecológicas necesarias para la protección y conservación del Sur de Fuerteventura (Montes de Amanay y El Banquete)El proyecto INDEMARES ha permitido utilizar amplios medios económicos y personales para estudiar en detalle y desde múltiples perspectivas la zona del Sur de Fuerteventura (montes de Amanay y El Banquete). Se han aplicado metodologías para el estudio de la hidrografía, caracterizando la región, describiendo sus principales masas de agua y la hidrodinámica de las corrientes. También se ha abordado la geología de la zona, incluyendo levantamientos batimétricos, perfiles sísmicos, muestreos de sedimento y petrológicos, obteniendo modelos digitales del terreno, mapas de tipos de fondo, geomorfológicos. Se han caracterizado las comunidades bentopelágicas, demersales, epibentónicas y endobentónicas, prestando especial atención a aquellas que conforman o estructuran los hábitats sensibles cuyo inventariado y cartografía era objeto principal del proyecto. Los trabajos de identificación de hábitats se han realizado con muestreadores directos, pero también con muestreadores visuales, que han permitido hacer un mayor esfuerzo de muestreo sin aumentar el impacto sobre los fondos de la zona. Por otro lado se ha estudiado la huella pesquera de la zona por medio del análisis de los datos VMS y los cuadernos de pesca proporcionados por la SGP, además de una ardua labor a pie de puerto de entrevistas y encuestas. Toda la información ha sido gestionada y analizada por diferentes grupos de investigación de diferentes centros (Universidad de La Laguna, Instituto Universitario de Ciencias Políticas y Sociales, Universidad de Las Palmas de Gran Canaria, Instituto de Ciencias del Mar de Barcelona, Universidad de Barcelona, Centro de Investigaciones Medioambientales del Atlántico, Centro Oceanográfico de Santander y Centro Oceanográfico de Málaga del Instituto Español de Oceanografía, …), aunque el grueso de esta labor, además de la coordinación, se ha llevado a cabo en el Centro Oceanográfico de Canarias del Instituto Español de Oceanografía. Los resultados permiten tener un conocimiento profundo y multidisciplinar de la zona de estudio comparable a pocos proyectos de investigación marina en la Macaronesia. El estudio oceanográfico, el geológico, y el de las comunidades biológicas, ha permitido la caracterización de los hábitats de la zona, y su cartografiado mediante el intenso muestreo y la aplicación de análisis de idoneidad de hábitats.Abstract: INDEMARES Project made possible to bring together economic and staff resources to study in detail, and from multiple perspectives, the area of South of Fuerteventura (Amanay and El Banquete Semounts). Methodologies have been applied to study hydrography, making a regional characterization, depicting main water masses, and current hydrodynamics. Geology has been tackled including bathymetric uplifting, seismic profiles, sediment and petrological sampling, obtaining digital terrain models, type of bottom maps, geomorphological maps, as an output. Benthopelagic, demersal, epibenthic and endobenthic communities have been characterized, paying special attention to sensitive habitats which inventory and mapping was the project’s main aim. Habitat identification has been made with direct and visual samplers, the latter making a major sampling effort possible without an increase of bottom impact. Moreover, fisheries footprint has been identified by Vessel Monitoring System data, together with logbooks from Secretaría General de Pesca (Fisheries Ministry), as well as a hard interviewing and surveying task at landing points. Information has been managed and analysed by different research groups from different Centres (Universidad de La Laguna, Instituto Universitario de Ciencias Políticas y Sociales, Universidad de Las Palmas de Gran Canaria, Instituto de Ciencias del Mar de Barcelona, Universidad de Barcelona, Centro de Investigaciones Medioambientales del Atlántico, Centro Oceanográfico de Santander y Centro Oceanográfico de Málaga del Instituto Español de Oceanografía), although the main body of the work, plus coordination, has been made by the Canary Islands Oceanographic Centre, from the Spanish Institute of Oceanography. Results let us have a multidisciplinary profound knowledge of the study zone, comparable to few other marine research projects off Macaronesia. The study about oceanography, geology and biologic communities has allowed the habitats characterization and mapping by means of intensive sampling and habitat suitability analysis.Instituto Español de Oceanografía, Comisión Europea Programa LIFE+, Fundación Biodiversida

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Treatment of COVID-19 during the Acute Phase in Hospitalized Patients Decreases Post-Acute Sequelae of COVID-19

Background: The post-acute sequelae of SARS-CoV-2 (PASC) infection have caused a significant impact on our health system, but there is limited evidence of approved drugs focused on its prevention. Our objective was to identify risk factors that can determine the presence of PASC, with special attention to the treatment received in the acute phase, and to describe the profile of persistent symptoms in a multidisciplinary Post-Coronavirus Disease-19 (COVID-19) Unit. Methods: This one-year prospective observational study included patients following an acute COVID-19 infection, irrespective of whether they required hospital admission. A standardized symptom questionnaire and blood sampling were performed at the first follow-up visit, and demographic and clinical electronic data were collected. We compared subjects with PASC with those who had fully recovered. Multivariate logistic regression was performed to identify factors associated with PASC in hospitalized patients, and Kaplan–Meier curves were used to assess duration of symptoms according to disease severity and treatments received in the acute phase. Results: 1966 patients were evaluated; 1081 had mild disease, 542 moderate and 343 severe; around one third of the subjects had PASC, and were more frequently female, with obesity, asthma, and eosinophilia during acute COVID-19 disease. Patients who received treatment with dexamethasone and remdesivir during the course of the acute illness showed a lower median duration of symptoms, compared with those who received none of these treatments. Conclusion: Treatment with dexamethasone and/or remdesivir may be useful to reduce the impact of PASC secondary to SARS-CoV-2 infection. In addition, we identified female gender, obesity, asthma, and disease severity as risk factors for having PASC