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BACKGROUND AND AIMS: Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. METHODS: Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2â mg/L). RESULTS: Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2â mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2â mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2â mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). CONCLUSIONS: While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.
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Proteína C-Reactiva , Enfermedad Coronaria , Humanos , Proteína C-Reactiva/metabolismo , Estudios Prospectivos , Factores de Riesgo , Lipoproteína(a) , Enfermedad Coronaria/epidemiología , Biomarcadores/metabolismoRESUMEN
Depletion or mutations of key proteins for mitochondrial fusion, like optic atrophy 1 (OPA1) and mitofusins 1 and 2 (Mfn 1 and 2), are known to significantly impact the mitochondrial ultrastructure, suggesting alterations of their membranes' lipid profiles. In order to make an insight into this issue, we used hydrophilic interaction liquid chromatography coupled with electrospray ionization-high resolution MS to investigate the mitochondrial phospholipid (PL) profile of mouse embryonic fibroblasts knocked out for OPA1 and Mfn1/2 genes. One hundred sixty-seven different sum compositions were recognized for the four major PL classes of mitochondria, namely phosphatidylcholines (PCs, 63), phosphatidylethanolamines (55), phosphatidylinositols (21), and cardiolipins (28). A slight decrease in the cardiolipin/PC ratio was found for Mfn1/2-knockout mitochondria. Principal component analysis and hierarchical cluster analysis were subsequently used to further process hydrophilic interaction liquid chromatography-ESI-MS data. A progressive decrease in the incidence of alk(en)yl/acyl species in PC and phosphatidylethanolamine classes and a general increase in the incidence of unsaturated acyl chains across all the investigated PL classes was inferred in OPA1 and Mfn1/2 knockouts compared to WT mouse embryonic fibroblasts. These findings suggest a reshaping of the PL profile consistent with the changes observed in the mitochondrial ultrastructure when fusion proteins are absent. Based on the existing knowledge on the metabolism of mitochondrial phospholipids, we propose that fusion proteins, especially Mfns, might influence the PL transfer between the mitochondria and the endoplasmic reticulum, likely in the context of mitochondria-associated membranes.
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GTP Fosfohidrolasas , Lipidómica , Mitocondrias , Fosfolípidos , Animales , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/deficiencia , Ratones , Mitocondrias/metabolismo , Fosfolípidos/metabolismo , Ratones Noqueados , Fibroblastos/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genéticaRESUMEN
Mitochondrial carriers (MCs) belong to a eukaryotic protein family of transporters that in higher organisms is called the solute carrier family 25 (SLC25). All MCs have characteristic triplicated sequence repeats forming a 3-fold symmetrical structure of a six-transmembrane α-helix bundle with a centrally located substrate-binding site. Biochemical characterization has shown that MCs altogether transport a wide variety of substrates but can be divided into subfamilies, each transporting a few specific substrates. We have investigated the intron positions in the human MC genes and their orthologs of highly diversified organisms. The results demonstrate that several intron positions are present in numerous MC sequences at the same specific points, of which some are 3-fold symmetry related. Many of these frequent intron positions are also conserved in subfamilies or in groups of subfamilies transporting similar substrates. The analyses of the frequent and conserved intron positions in MCs suggest phylogenetic relationships not only between close but also distant homologs as well as a possible involvement of the intron positions in the evolution of the substrate specificity diversification of the MC family members.
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Proteínas de Transporte de Membrana , Mitocondrias , Humanos , Intrones , Filogenia , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana/genética , Eucariontes/genética , Evolución Molecular , Secuencia ConservadaRESUMEN
The aim of this paper is to contribute technical arguments to the debate about the importance of health examination surveys and their continued use during the post-pandemic health financing crisis, and in the context of a technological innovation boom that offers new ways of collecting and analysing individual health data (e.g. artificial intelligence). Technical considerations demonstrate that health examination surveys make an irreplaceable contribution to the local availability of primary health data that can be used in a range of further studies (e.g. normative, burden-of-disease, care cascade, cost and policy impact studies) essential for informing several phases of the health planning cycle (e.g. surveillance, prioritization, resource mobilization and policy development). Examples of the use of health examination survey data in the World Health Organization (WHO) European Region (i.e. Finland, Italy, Malta and the United Kingdom of Great Britain and Northern Ireland) and the WHO Region of the Americas (i.e. Chile, Mexico, Peru and the United States of America) are presented, and reasons why health provider-led data cannot replace health examination survey data are discussed (e.g. underestimation of morbidity and susceptibility to bias). In addition, the importance of having nationally representative random samples of the general population is highlighted and we argue that health examination surveys make a critical contribution to external quality control for a country's health system by increasing the transparency and accountability of health spending. Finally, we consider future technological advances that can improve survey fieldwork and suggest ways of ensuring health examination surveys are sustainable in low-resource settings.
Cet article a pour objet d'apporter des arguments techniques au débat sur l'importance des enquêtes de santé par examen et sur leur utilisation continue pendant la crise post-pandémique du financement de la santé et dans le contexte d'un essor de l'innovation technologique qui offre de nouvelles façons de collecter et d'analyser les données individuelles sur la santé (comme l'intelligence artificielle). Les considérations techniques démontrent que les enquêtes de santé par examen apportent une contribution irremplaçable à la disponibilité locale de données de santé primaires qui peuvent servir dans une série d'études complémentaires (telles que des études normatives, sur la charge de morbidité, la cascade des soins, les coûts et l'impact des politiques). Ces études sont essentielles pour renseigner plusieurs phases du cycle de planification sanitaire (par exemple: surveillance, priorisation, mobilisation de ressources et élaboration de politiques). Cet article présente des exemples d'utilisation des données d'enquêtes de santé par examen dans la Région OMS de l'Europe (Finlande, Italie, Malte et Royaume-Uni de Grande-Bretagne et d'Irlande du Nord) et dans la Région OMS des Amériques (Chili, États-Unis d'Amérique, Mexique et Pérou) et aborde les raisons pour lesquelles les données fournies par les prestataires de soins de santé ne peuvent pas remplacer les données d'enquêtes de santé par examen (par exemple la sous-estimation de la morbidité et la vulnérabilité aux biais). En outre, il soulignet l'importance de disposer d'échantillons aléatoires représentatifs de la population générale au niveau national, et nous soutenons que les enquêtes de santé par examen apportent une contribution essentielle au contrôle externe de la qualité du système de santé d'un pays en renforçant la transparence des dépenses de santé et l'obligation de rendre des comptes à leur sujet. Enfin, nous envisageons les futures avancées technologiques susceptibles d'améliorer le travail d'enquête sur le terrain et suggérons des moyens d'assurer la viabilité des enquêtes de santé par examen dans les environnements à faibles ressources.
El objetivo de este artículo es aportar argumentos técnicos al debate sobre la importancia de las encuestas de salud y su uso continuado durante la crisis de financiación sanitaria pospandémica y en el contexto de un auge de la innovación tecnológica que ofrece nuevas formas de recopilar y analizar datos sanitarios individuales (por ejemplo, la inteligencia artificial). Las consideraciones técnicas demuestran que las encuestas de salud contribuyen de manera insustituible a la disponibilidad local de datos sanitarios primarios que pueden utilizarse en toda una serie de estudios posteriores (por ejemplo, estudios normativos, de carga de morbilidad, de cascada asistencial, de costes y de impacto de las políticas) esenciales para fundamentar varias fases del ciclo de planificación sanitaria (por ejemplo, vigilancia, establecimiento de prioridades, movilización de recursos y elaboración de políticas). Se presentan ejemplos del uso de los datos de las encuestas de salud en la Región Europea de la Organización Mundial de la Salud (Finlandia, Italia, Malta y el Reino Unido de Gran Bretaña e Irlanda del Norte) y en la Región de las Américas de la OMS (Chile, Estados Unidos de América, México y Perú) y se analizan las razones por las que los datos obtenidos por los proveedores sanitarios no pueden sustituir a los de las encuestas de salud (por ejemplo, la subestimación de la morbilidad y la posibilidad de sesgo). Además, se destaca la importancia de contar con muestras aleatorias representativas de la población general a escala nacional y se argumenta que las encuestas de salud contribuyen de forma decisiva al control de calidad externo del sistema sanitario de un país, al aumentar la transparencia y la rendición de cuentas del gasto sanitario. Por último, se examinan los futuros avances tecnológicos que pueden mejorar el trabajo de campo de las encuestas y se sugieren métodos para garantizar que las encuestas de salud sean sostenibles en entornos con pocos recursos.
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Organización Mundial de la Salud , Humanos , Encuestas Epidemiológicas , COVID-19/epidemiología , Salud GlobalRESUMEN
BACKGROUND: Contact tracing is a public health intervention implemented in synergy with other preventive measures to curb epidemics, like the coronavirus pandemic. The development and use of digital devices have increased worldwide to enhance the contact tracing process. The aim of the study was to evaluate the effectiveness and impact of tracking coronavirus disease 2019 (COVID-19) patients using digital solutions. METHODS: Observational studies on digital contact tracing (DCT), published 2020-21, in English were identified through a systematic literature review performed on nine online databases. An ad hoc form was used for data extraction of relevant information. Quality assessment of the included studies was performed with validated tools. A qualitative synthesis of the findings is reported. RESULTS: Over 8000 records were identified and 37 were included in the study: 24 modelling and 13 population-based studies. DCT improved the identification of close contacts of COVID-19 cases and reduced the effective reproduction number of COVID-19-related infections and deaths by over 60%. It impacted positively on societal and economic costs, in terms of lockdowns and use of resources, including staffing. Privacy and security issues were reported in 27 studies. CONCLUSIONS: DCT contributed to curbing the COVID-19 pandemic, especially with the high uptake rate of the devices and in combination with other public health measures, especially conventional contact tracing. The main barriers to the implementation of the devices are uptake rate, security and privacy issues. Public health digitalization and contact tracing are the keys to countries' emergency preparedness for future health crises.
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COVID-19 , Trazado de Contacto , Pandemias , SARS-CoV-2 , COVID-19/prevención & control , COVID-19/epidemiología , Humanos , Trazado de Contacto/métodos , Pandemias/prevención & control , Tecnología Digital , Salud Pública/métodosRESUMEN
BACKGROUND: Timely and high-quality population-level health information is needed to support evidence-informed decision-making, for planning and evaluation of prevention, care and cure activities as well as for research to generate new knowledge. FAIR (Findable, Accessible, Interoperable and Reusable) principles are one of the key elements supporting health research and making it more cost-effective through the reuse of already existing data. Currently, health data are in many countries dispersed and difficult to find and access. METHODS: Two EU Public Health Programmes co-funded Joint Actions, Information for Action (InfAct) and Population Health Information Research Infrastructure (PHIRI) have established a European Health Information Portal, a web-based service, to facilitate better findability, access, interoperability and reuse of existing health information. RESULTS: The European Health Information Portal (www.healthinformationportal.eu) has been established including sections on National Nodes, data sources, publications, health information projects within countries and across Europe, research networks and research infrastructures, ethical and legal issues for health information exchange and use, capacity-building activities in all areas of population health and a dedicated COVID-19 section. CONCLUSIONS: The European Health Information Portal, being a central place for a wide range of population health information from EU Member States, is an information source for researchers, policy-makers and other relevant stakeholders. It is important to ensure the sustainability of the portal, especially in light of the European Health Data Space (EHDS) Regulation proposal and its requirements regarding the secondary use of health data.
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COVID-19 , Humanos , Europa (Continente) , COVID-19/prevención & control , SARS-CoV-2 , Difusión de la Información/métodos , Salud Pública , Unión EuropeaRESUMEN
BACKGROUND: During the first epidemic wave, COVID-19 surveillance focused on quantifying the magnitude and the escalation of a growing global health crisis. The scientific community first assessed risk through basic indicators, such as the number of cases or rates of new cases and deaths, and later began using other direct impact indicators to conduct more detailed analyses. We aimed at synthesizing the scientific community's contribution to assessing the direct impact of the COVID-19 pandemic on population health through indicators reported in research papers. METHODS: We conducted a rapid scoping review to identify and describe health indicators included in articles published between January 2020 and June 2021, using one strategy to search PubMed, EMBASE and WHO COVID-19 databases. Sixteen experts from European public health institutions screened papers and retrieved indicator characteristics. We also asked in an online survey how the health indicators were added to and used in policy documents in Europe. RESULTS: After reviewing 3891 records, we selected a final sample of 67 articles and 233 indicators. We identified 52 (22.3%) morbidity indicators from 33 articles, 105 severity indicators (45.1%, 27 articles) and 68 mortality indicators (29.2%, 51). Respondents from 22 countries completed 31 questionnaires, and the majority reported morbidity indicators (29, 93.5%), followed by mortality indicators (26, 83.9%). CONCLUSIONS: The indicators collated here might be useful to assess the impact of future pandemics. Therefore, their measurement should be standardized to allow for comparisons between settings, countries and different populations.
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COVID-19 , Humanos , COVID-19/mortalidad , COVID-19/epidemiología , Europa (Continente)/epidemiología , Indicadores de Salud , Morbilidad , Mortalidad/tendencias , Pandemias , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The indirect impact of the coronavirus disease 2019 pandemic on healthcare services was studied by assessing changes in the trend of the time to first treatment for women 18 or older who were diagnosed and treated for breast cancer between 2017 and 2021. METHODS: An observational retrospective longitudinal study based on aggregated data from four European Union (EU) countries/regions investigating the time it took to receive breast cancer treatment. We compiled outputs from a federated analysis to detect structural breakpoints, confirming the empirical breakpoints by differences between the trends observed and forecasted after March 2020. Finally, we built several segmented regressions to explore the association of contextual factors with the observed changes in treatment delays. RESULTS: We observed empirical structural breakpoints on the monthly median time to surgery trend in Aragon (ranging from 9.20 to 17.38 days), Marche (from 37.17 to 42.04 days) and Wales (from 28.67 to 35.08 days). On the contrary, no empirical structural breakpoints were observed in Belgium (ranging from 21.25 to 23.95 days) after the pandemic's beginning. Furthermore, we confirmed statistically significant differences between the observed trend and the forecasts for Aragon and Wales. Finally, we found the interaction between the region and the pandemic's start (before/after March 2020) significantly associated with the trend of delayed breast cancer treatment at the population level. CONCLUSIONS: Although they were not clinically relevant, only Aragon and Wales showed significant differences with expected delays after March 2020. However, experiences differed between countries/regions, pointing to structural factors other than the pandemic.
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Neoplasias de la Mama , COVID-19 , SARS-CoV-2 , Tiempo de Tratamiento , Humanos , COVID-19/epidemiología , Neoplasias de la Mama/terapia , Femenino , Estudios Longitudinales , Estudios Retrospectivos , Tiempo de Tratamiento/estadística & datos numéricos , Persona de Mediana Edad , Pandemias , Adulto , Anciano , Unión Europea , Salud Poblacional , Retraso del TratamientoRESUMEN
BACKGROUND: Resilience of national health systems in Europe remains a major concern in times of multiple crises and as more evidence is emerging relating to the indirect effects of the COVID-19 pandemic on health care utilization (HCU), resulting from de-prioritization of regular, non-pandemic healthcare services. Most extant studies focus on regional, disease specific or early pandemic HCU creating difficulties in comparing across multiple countries. We provide a comparatively broad definition of HCU across multiple countries, with potential to expand across regions and timeframes. METHODS: Using a cross-country federated research infrastructure (FRI), we examined HCU for acute cardiovascular events, elective surgeries and serious trauma. Aggregated data were used in forecast modelling to identify changes from predicted European age-standardized counts via fitted regressions (2017-19), compared against post-pandemic data. RESULTS: We found that elective surgeries were most affected, universally falling below predicted levels in 2020. For cardiovascular HCU, we found lower-than-expected cases in every region for heart attacks and displayed large sex differences. Serious trauma was the least impacted by the COVID-19 pandemic. CONCLUSION: The strength of this study comes from the use of the European Population Health Information Research Infrastructure's (PHIRI) FRI, allowing for rapid analysis of regional differences to assess indirect impacts of events such as pandemics. There are marked differences in the capacity of services to return to normal in terms of elective surgery; additionally, we found considerable differences between men and women which requires further research on potential sex or gender patterns of HCU during crises.
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COVID-19 , Procedimientos Quirúrgicos Electivos , Aceptación de la Atención de Salud , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Europa (Continente)/epidemiología , Masculino , Femenino , Estudios Retrospectivos , Aceptación de la Atención de Salud/estadística & datos numéricos , Procedimientos Quirúrgicos Electivos/estadística & datos numéricos , Pandemias , Persona de Mediana Edad , Adulto , Anciano , Heridas y Lesiones/epidemiología , Enfermedades Cardiovasculares/epidemiologíaRESUMEN
Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164â¯054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17â¯211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.
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Biomarcadores , Enfermedades Cardiovasculares , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Troponina I , Troponina T , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aterosclerosis/sangre , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/mortalidad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Troponina I/sangre , Troponina T/sangre , InternacionalidadRESUMEN
BACKGROUND: Mitochondrial carriers (MCs) can deeply affect the intracellular flux distribution of metabolic pathways. The manipulation of their expression level, to redirect the flux toward the production of a molecule of interest, is an attractive target for the metabolic engineering of eukaryotic microorganisms. The non-conventional yeast Yarrowia lipolytica is able to use a wide range of substrates. As oleaginous yeast, it directs most of the acetyl-CoA therefrom generated towards the synthesis of lipids, which occurs in the cytoplasm. Among them, the odd-chain fatty acids (OCFAs) are promising microbial-based compounds with several applications in the medical, cosmetic, chemical and agricultural industries. RESULTS: In this study, we have identified the MC involved in the Carnitine/Acetyl-Carnitine shuttle in Y. lipolytica, YlCrc1. The Y. lipolytica Ylcrc1 knock-out strain failed to grow on ethanol, acetate and oleic acid, demonstrating the fundamental role of this MC in the transport of acetyl-CoA from peroxisomes and cytoplasm into mitochondria. A metabolic engineering strategy involving the deletion of YlCRC1, and the recombinant expression of propionyl-CoA transferase from Ralstonia eutropha (RePCT), improved propionate utilization and its conversion into OCFAs. These genetic modifications and a lipogenic medium supplemented with glucose and propionate as the sole carbon sources, led to enhanced accumulation of OCFAs in Y. lipolytica. CONCLUSIONS: The Carnitine/Acetyl-Carnitine shuttle of Y. lipolytica involving YlCrc1, is the sole pathway for transporting peroxisomal or cytosolic acetyl-CoA to mitochondria. Manipulation of this carrier can be a promising target for metabolic engineering approaches involving cytosolic acetyl-CoA, as demonstrated by the effect of YlCRC1 deletion on OCFAs synthesis.
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Carnitina , Yarrowia , Acetilcoenzima A/metabolismo , Carnitina/metabolismo , Acetilcarnitina/metabolismo , Yarrowia/genética , Yarrowia/metabolismo , Ácidos Grasos/metabolismo , Propionatos/metabolismo , Mitocondrias/metabolismo , Ingeniería MetabólicaRESUMEN
Mitochondrial RTG (an acronym for ReTroGrade) signaling plays a cytoprotective role under various intracellular or environmental stresses. We have previously shown its contribution to osmoadaptation and capacity to sustain mitochondrial respiration in yeast. Here, we studied the interplay between RTG2, the main positive regulator of the RTG pathway, and HAP4, encoding the catalytic subunit of the Hap2-5 complex required for the expression of many mitochondrial proteins that function in the tricarboxylic acid (TCA) cycle and electron transport, upon osmotic stress. Cell growth features, mitochondrial respiratory competence, retrograde signaling activation, and TCA cycle gene expression were comparatively evaluated in wild type and mutant cells in the presence and in the absence of salt stress. We showed that the inactivation of HAP4 improved the kinetics of osmoadaptation by eliciting both the activation of retrograde signaling and the upregulation of three TCA cycle genes: citrate synthase 1 (CIT1), aconitase 1 (ACO1), and isocitrate dehydrogenase 1 (IDH1). Interestingly, their increased expression was mostly dependent on RTG2. Impaired respiratory competence in the HAP4 mutant does not affect its faster adaptive response to stress. These findings indicate that the involvement of the RTG pathway in osmostress is fostered in a cellular context of constitutively reduced respiratory capacity. Moreover, it is evident that the RTG pathway mediates peroxisomes-mitochondria communication by modulating the metabolic function of mitochondria in osmoadaptation.
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Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ciclo del Ácido Cítrico/genética , Citrato (si)-Sintasa/metabolismo , Transducción de Señal , Regulación Fúngica de la Expresión GénicaRESUMEN
Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD+ , which are all structurally similar to nucleotides and derived from different B-vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease-causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactor-dependent enzymes are involved. The mitochondrial transport, metabolism and diseases of the cofactors thiamine pyrophosphate, coenzyme A, FAD and NAD+ are the focus of this review.
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Coenzima A , Tiamina Pirofosfato , Flavina-Adenina Dinucleótido/metabolismo , NAD/metabolismo , Tiamina Pirofosfato/metabolismo , VitaminasRESUMEN
S-adenosyl-L-methionine (SAM) is a coenzyme and the most commonly used methyl-group donor for the modification of metabolites, DNA, RNA and proteins. SAM biosynthesis and SAM regeneration from the methylation reaction product S-adenosyl-L-homocysteine (SAH) take place in the cytoplasm. Therefore, the intramitochondrial SAM-dependent methyltransferases require the import of SAM and export of SAH for recycling. Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1-2 in plants. In mitochondria SAM is used by a vast number of enzymes implicated in the following processes: the regulation of replication, transcription, translation, and enzymatic activities; the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin. Mutations in SLC25A26 and mitochondrial SAM-dependent enzymes have been found to cause human diseases, which emphasizes the physiological importance of these proteins.
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Mitocondrias , S-Adenosilmetionina , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Transporte Biológico , Proteínas de Unión al Calcio/metabolismo , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , S-Adenosilmetionina/metabolismoRESUMEN
Even though sunlight is viewed as the most important determinant of 25-hydroxyvitamin D (25(OH)D) status, several European studies have observed higher 25(OH)D concentrations among north-Europeans than south-Europeans. We studied the association between geographical latitude (derived from ecological data) and 25(OH)D status in six European countries using harmonised immunoassay data from 81 084 participants in the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project (male sex 48·9 %; median age 50·8 years; examination period 1984-2014). Quantile regression models, adjusted for age, sex, decade and calendar week of sampling and time from sampling to analysis, were used for between-country comparisons. Up until the median percentile, the ordering of countries by 25(OH)D status (from highest to lowest) was as follows: Sweden (at 65·6-63·8°N), Germany (at 48·4°N), Finland (at 65·0-60·2°N), Italy (at 45·6-41·5°N), Scotland (at 58·2-55·1°N) and Spain (at 41·5°N). From the 75th percentile and upwards, Finland had higher values than Germany. As an example, using the Swedish cohort as a comparator, the median 25(OH)D concentration was 3·03, 3·28, 5·41, 6·54 and 9·28 ng/ml lower in the German, Finnish, Italian, Scottish and Spanish cohort, respectively (P-value < 0·001 for all comparisons). The ordering of countries was highly consistent in subgroup analyses by sex, age, and decade and season of sampling. In conclusion, we confirmed the previous observation of a north-to-south gradient of 25(OH)D status in Europe, with higher percentile values among north-Europeans than south-Europeans.
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Deficiencia de Vitamina D , Vitamina D , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores , Estudios Transversales , Europa (Continente)/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Estaciones del Año , Vitamina D/análisis , Deficiencia de Vitamina D/epidemiología , Femenino , GeografíaRESUMEN
Mitochondrial carriers, which transport metabolites, nucleotides, and cofactors across the mitochondrial inner membrane, have six transmembrane α-helices enclosing a translocation pore with a central substrate binding site whose access is controlled by a cytoplasmic and a matrix gate (M-gate). The salt bridges formed by the three PX[DE]XX[RK] motifs located on the odd-numbered transmembrane α-helices greatly contribute to closing the M-gate. We have measured the transport rates of cysteine mutants of the charged residue positions in the PX[DE]XX[RK] motifs of the bovine oxoglutarate carrier, the yeast GTP/GDP carrier, and the yeast NAD+ transporter, which all lack one of these charged residues. Most single substitutions, including those of the non-charged and unpaired charged residues, completely inactivated transport. Double mutations of charged pairs showed that all three carriers contain salt bridges non-essential for activity. Two double substitutions of these non-essential charge pairs exhibited higher transport rates than their corresponding single mutants, whereas swapping the charged residues in these positions did not increase activity. The results demonstrate that some of the residues in the charged residue positions of the PX[DE]XX[KR] motifs are important for reasons other than forming salt bridges, probably for playing specific roles related to the substrate interaction-mediated conformational changes leading to the M-gate opening/closing.
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Proteínas de Transporte de Membrana Mitocondrial , Membranas Mitocondriales , Proteínas Mitocondriales , Secuencias de Aminoácidos/fisiología , Animales , Bovinos , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Conformación Proteica en Hélice alfa/fisiología , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Uncoupling proteins (UCPs) form a distinct subfamily of the mitochondrial carrier family (MCF) SLC25. Four UCPs, DmUCP4A-C and DmUCP5, have been identified in Drosophila melanogaster on the basis of their sequence homology with mammalian UCP4 and UCP5. In a Parkinson's disease model, DmUCP4A showed a protective role against mitochondrial dysfunction, by increasing mitochondrial membrane potential and ATP synthesis. To date, DmUCP4A is still an orphan of a biochemical function, although its possible involvement in mitochondrial uncoupling has been ruled out. Here, we show that DmUCP4A expressed in bacteria and reconstituted in phospholipid vesicles catalyzes a unidirectional transport of aspartate, which is saturable and inhibited by mercurials and other mitochondrial carrier inhibitors to various degrees. Swelling experiments carried out in yeast mitochondria have demonstrated that the unidirectional transport of aspartate catalyzed by DmUCP4 is not proton-coupled. The biochemical function of DmUCP4A has been further confirmed in a yeast cell model, in which growth has required an efflux of aspartate from mitochondria. Notably, DmUCP4A is the first UCP4 homolog from any species to be biochemically characterized. In Drosophila melanogaster, DmUCP4A could be involved in the transport of aspartate from mitochondria to the cytosol, in which it could be used for protein and nucleotide synthesis, as well as in the biosynthesis of ß-alanine and N-acetylaspartate, which play key roles in signal transmission in the central nervous system.
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Ácido Aspártico/metabolismo , Drosophila melanogaster/metabolismo , Proteínas Desacopladoras Mitocondriales/genética , Proteínas Desacopladoras Mitocondriales/metabolismo , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/biosíntesis , Transporte Biológico Activo , Clonación Molecular , Citosol/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Mitocondrias/metabolismo , beta-Alanina/biosíntesisRESUMEN
During cultivation under nitrogen starvation, Yarrowia lipolytica produces a mixture of citric acid and isocitric acid whose ratio is mainly determined by the carbon source used. We report that mitochondrial succinate-fumarate carrier YlSfc1 controls isocitric acid efflux from mitochondria. YlSfc1 purified and reconstituted into liposomes transports succinate, fumarate, oxaloacetate, isocitrate and α-ketoglutarate. YlSFC1 overexpression determined the inversion of isocitric acid/citric acid ratio towards isocitric acid, resulting in 33.4 ± 1.9 g/L and 43.3 ± 2.8 g/L of ICA production in test-tube cultivation with glucose and glycerol, respectively. These titers represent a 4.0 and 6.3-fold increase compared to the wild type. YlSFC1 gene expression was repressed in the wild type strain grown in glucose-based medium compared to olive oil medium explaining the reason for the preferred citric acid production during Y. lipolytica growth on carbohydrates. Coexpression of YlSFC1 and adenosine monophosphate deaminase YlAMPD genes together with inactivation of citrate mitochondrial carrier YlYHM2 gene enhanced isocitric acid accumulation up to 41.4 ± 4.1 g/L with an isocitric acid/citric acid ratio of 14.3 in a small-scale cultivation with glucose as a carbon source. During large-scale cultivation with glucose pulse-feeding, the engineered strain produced 136.7 ± 2.5 g/L of ICA with a process selectivity of 88.1%, the highest reported titer and selectivity to date. These results represent the first reported isocitric acid secretion by Y. lipolytica as a main organic acid during cultivation on carbohydrate. Moreover, we demonstrate for the first time that the replacement of one mitochondrial transport system for another can be an efficient tool for switching product accumulation.
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Yarrowia , Transportadores de Ácidos Dicarboxílicos/genética , Isocitratos , Mitocondrias/genética , Yarrowia/genéticaRESUMEN
BACKGROUND AND AIMS: Low potassium intake, in addition to high sodium, has been associated with higher risk of hypertension and CVD. The Study assessed habitual potassium intake and sodium/potassium ratio of the Italian adult population from 2008 to 2012 to 2018-2019 based on 24-h urine collection, in the framework of the CUORE Project/MINISAL-GIRCSI/MENO SALE PIU' SALUTE national surveys. METHODS AND RESULTS: Data were from cross-sectional surveys of randomly selected age-and-sex stratified samples of resident persons aged 35-74 years in 10 (out of 20) Italian regions. Urinary electrolyte and creatinine measurements were performed in a central laboratory. Analyses considered 942 men and 916 women, examined in 2008-2012, and 967 men and 1010 women, examined in 2018-2019. In 2008-2012, the age-standardized mean of potassium intake (urinary potassium accounts for 70% of potassium intake) was 3147 mg (95% CI 3086-3208) in men and 2784 mg (2727-2841) in women, whereas in 2018-2019, it was 3043 mg (2968-3118) and 2561 mg (2508-2614) respectively. In 2008-2012, age-adjusted prevalence of persons with an adequate potassium intake (i.e. ≥ 3510 mg/day) was 31% (95% CI 28-34%) for men and 18% (16-21%) for women; in 2018-2019, it was 26% (23-29%) and 12% (10-14%) respectively. The sodium/potassium ratio significantly decreased both in men and women. CONCLUSIONS: The average daily potassium intake of the Italian general adult population remains lower than the WHO and EFSA recommended level. These results suggest the need of a revision to strengthen initiatives for the promotion of an adequate potassium intake at the population level.
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Dieta/tendencias , Potasio en la Dieta/orina , Sodio en la Dieta/orina , Adulto , Anciano , Estudios Transversales , Encuestas sobre Dietas , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Estado Nutricional , Ingesta Diaria Recomendada , Eliminación Renal , Factores de Tiempo , UrinálisisRESUMEN
BACKGROUND AND AIMS: The WHO Global Action Plan for the Prevention of non-communicable diseases (NCDs) recommends a 30% relative reduction in mean population salt/sodium intake. The study assessed the trend in the habitual salt intake of the Italian adult population from 2008 to 2012 to 2018-2019 based on 24-h urinary sodium excretion, in the framework of the CUORE Project/MINISAL-GIRCSI/MENO SALE PIU' SALUTE national surveys. METHODS AND RESULTS: Data were from cross-sectional surveys of randomly selected age and sex-stratified samples of resident persons aged 35-74 years in 10 (out of 20) Italian Regions distributed in North, Centre and South of the Country. Urinary sodium and creatinine measurements were carried out in a central laboratory. The analyses included 942 men and 916 women examined in 2008-2012, and 967 men and 1010 women examined in 2018-2019. The age-standardized mean daily population salt (sodium chloride) intake was 10.8 g (95% CI 10.5-11.1) in men and 8.3 g (8.1-8.5) in women in 2008-2012 and respectively 9.5 g (9.3-9.8) and 7.2 g (7.0-7.4) in 2018-2019. A statistically significant (p<0.0001) salt intake reduction was thus observed over 10 years for both genders, and all age, body mass index (BMI) and educational classes. CONCLUSIONS: The average daily salt intake of the Italian general adult population remains higher than the WHO recommended level, but a significant reduction of 12% in men and 13% in women has occurred in the past ten years. These results encourage the initiatives undertaken by the Italian Ministry of Health aimed at the reduction of salt intake at the population level.