Articles publicats (Medicina Experimental)
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- ItemOpen AccessHakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS(Elsevier, 2023) Fernández Bernal, Anna; Mota Martorell, Natàlia; Pamplona Gras, Reinald; Area Gomez, Estela; Portero Otín, ManuelAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
- ItemOpen AccessPlasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome(Wiley, 2023) Sol, Joaquim; Obis Monné, Èlia; Mota Martorell, Natàlia; Pradas Barriga, Irene; Galo-Licona, José Daniel; Martín Garí, Meritxell; Fernández Bernal, Anna; Ortega Bravo, Marta; Mayneris Perxachs, Jordi; Borrás, Consuelo; Viña, José; Fuente, Monica de la; Mate, Ianire; Biarnés, Carles; Pedraza, Salvador; Vilanova, Joan Carles; Brugada, Ramon; Ramos, Rafel; Serena, Joaquín; Ramió Torrentà, Lluís; Pineda, Víctor; Daunis-i-Estadella, Pepus; Thió-Henestrosa, Santiago; Barretina Ginesta, Jordi; Garre Olmo, Josep; Portero Otín, Manuel; Fernández Real, José Manuel; Puig, Josep; Jové, Mariona; Pamplona Gras, ReinaldAging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of “omic” techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30–100 years old; 2: n = 68, 70% females, 19–107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial β-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.
- ItemOpen AccessGenetic Associations Between Modifiable Risk Factors and Alzheimer Disease(American Medical Association, 2023) Luo, Jiao; Qvist Thomassen, Jesper; Bellenguez, Céline; Grenier-Boley, Benjamin; De Rojas, Itziar; Castillo, Atahualpa; Parveen, Kayenat; Küçükali, Fahri; Nicolas, Aude; Peters, Oliver; Schneider, Anjal; Dichgans, Martin; Rujescu, Dan; Scherbaum, Norbert; Jürgen, Deckert; Riedel-Heller, Steffi; Hausner, Lucrezia; Molina Porcel, Laura; Düzel, Emrah; Grimmer, Timo; Wiltfang, Jens; Heilmann-Heimbach, Stefanie; Moebus, Susanne; Tegos, Thomas; Scarmeas, Nikolao; Clarimon, Jordi; Moreno, Fermin; Pérez-Tur, Jordi; Bullido, María J.; Pastor, Pau; Sánchez-Valle, Raquel; Álvarez, Victoria; Boada, Mercè; García-González, Pablo; Puerta, Raquel; Mir, Pablo; Real, Luis M.; Piñol-Ripoll, Gerard; García-Alberca, Jose María; Royo, Jose Luís; Rodriguez-Rodriguez, Eloy; Soininen, Hilkka; Kuulasmaa, Teemu; De Mendonça, Alexandre; Mehrabian, Shima; Hort, Jakub; Vyhnalek, Martin; Van Der Lee, Sven; Graff, Caroline; Papenberg, Goran; Giedraitis, Vilmantas; Boland, Anne; Bacq-Daian, Delphine; Deleuze, Jean-François; Nicolas, Gael; Dufouil, Carole; Pasquier, Florence; Hanon, Olivier; Debette, Stéphanie; Grünblatt, Edna; Popp, Julius; Benussi, Luisa; Galimberti, Daniela; Arosio, Beatrice; Mecocci, Patrizia; Solfrizzi, Vincenzo; Parnetti, Lucilla; Squassina, Alessio; Tremolizzo, Lucio; Borroni, Barbara; Nacmias, Benedetta; Sorbi, Sandro; Caffarra, Paolo; Seripa, Davide; Rainero, Innocenzo; Daniele, Antonio; Masullo, Carlo; Spalletta, Gianfranco; Williams, Julie; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick; Magda, Tsolaki; Rossi, Giacomina; Sánchez-Juan, Pascual; Sleegers, Kristel; Ingelsson, Martin; Andreassen, Ole A.; Hiltunen, Mikko; Van Duijn, Cornelia; Sims, Rebecca; Van Der Flier, Wiesje; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean-Charles; Frikke-Schmidt, RuthImportance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
- ItemOpen AccessSphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity(American Society for Clinical Investigation, 2023) Planas Serra, Laura; Launay, Nathalie; Goicoechea, Leire; Heron, Bénédicte; Jou, Cristina; Juliá Palacios, Natalia; Ruiz, Montserrat; Fourcade, Stéphane; Casasnovas, Carlos; de la Torre Gómez, Carolina; Gelot, Antoinette; Marsal, Maria; Loza-Alvarez, Pablo; García-Cazorla, Àngels; Fatemi, Ali; Ferrer, Isidre; Portero Otín, Manuel; Area-Gómez, Estela; Pujol, AuroraSphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.
- ItemOpen AccessEvolution and Development of Amygdala Subdivisions: Pallial, Subpallial, and Beyond(Karger Publishers, 2023-01) Medina Hernández, Loreta Mª; Abellán Ródenas, Antonio; Morales, Lorena; Pross, Alessandra; Metwalli, Alek H.; González Alonso, Alba; Freixes, Júlia; Desfilis, EsterThe amygdala is a central node in functional networks regulating emotions, social behavior, and social cognition. It develops in the telencephalon and includes pallial and subpallial parts, but these are extremely complex with multiple subdivisions, cell types, and connections. The homology of the amygdala in nonmammals is highly controversial, especially for the pallial part, and we are still far from understanding general principles on its organization that are common to different groups. Here, we review data on the adult functional architecture and developmental genoarchitecture of the amygdala in different amniotes (mammals and sauropsids), which are helping to disentangle and to better understand this complex structure. The use of an evolutionary developmental biology (evo-devo) approach has helped distinguish three major divisions in the amygdala, derived from the pallium, the subpallium, and from a newly identified division called telencephalon-opto-hypothalamic domain (TOH). This approach has also helped identify homologous cell populations with identical embryonic origins and molecular profiles in the amygdala of different amniotes. While subpallial cells produce different subtypes of GABAergic neurons, the pallium and TOH are major sources of glutamatergic cells. Available data point to a development-based molecular code that contributes to shape distinct functional subsystems in the amygdala, and comparative genoarchitecture is helping to delineate the cells involved in same subsystems in non-mammals. Thus, the evodevo approach can provide crucial information to understand common organizing principles of the amygdala cells and networks that control behavior, emotions, and cognition in amniotes.