Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19587

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Loss of SHP-1 in CD11c cells impairs anti-tumor immunity.
(FRONTIERS MEDIA, 2026) Galán, Miguel; Hernández-García, Elena; Munné, Pablo; Redondo-Urzainqui, Ana; Cueto, Francisco J; Sicilia, Jon; Alejano, Sergio Callejas; Rey-Martín, M Ascensión; Dopazo, Ana; Sancho, David; Iborra, Salvador
Tyrosine kinases and phosphatases regulate protein phosphorylation and maintain cellular homeostasis. The phosphoprotein tyrosine phosphatase SHP-1 (encoded by the gene) has been proposed as an immune checkpoint in CD8 T cells in preclinical models, yet its pharmacological inhibition has shown no efficacy against tumor growth in clinical trials. This suggests that SHP-1 may play opposing roles in different cell types within the tumor microenvironment. Here, we investigated the effect of depleting SHP-1 in CD11c cells on the anti-tumoral response. To dissect the specific role of SHP1 in CD11c antigen-presenting cells, or specifically in conventional type 1 dendritic cells (cDC1s) or macrophages, we subcutaneously inoculated different tumors in , Δ and Δ mice, respectively. Tumor growth and survival were monitored, and immune infiltrates were analyzed using flow cytometry or scRNA-seq. Tumor rejection was impaired when SHP-1 was depleted in CD11c cells, as well as in XCR1 or Lyz2 cells. scRNA-seq analysis revealed that both tumor-associated macrophages and cDC1s exhibited downregulation of interferon response pathways in tumor-bearing mice compared with controls. Reduced MHC-II expression in tumor-associated macrophages was validated by flow cytometry, supporting impaired antigen presentation in these cells, whereas cDC subsets displayed heterogeneous alterations in co-stimulatory marker expression rather than a defect. Consistent with these findings, flow cytometry analysis showed that mice injected with MC38 tumor and treated with anti-PD1 displayed a reduction in CD8 IFN-γ cells in comparison with littermates. These results show that SHP-1 depletion in CD11c cells impairs anti-tumor immunity and suggest that both cDC1s and macrophages contribute to this effect.
Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
(CELL PRESS, 2026-06-02) Heras-Murillo, Ignacio; Mañanes, Diego; Calafell-Segura, Josep; Belinchón García, Adrián; Borràs-Eroles, Clara; Munné, Pablo; Mastrangelo, Annalaura; Martínez-Cano, Sarai; Hernansanz-Agustín, Pablo; Zuriaga, María A; Fuster, José J; Szibor, Marten; Melero, Ignacio; Enríquez, José Antonio; Chandel, Navdeep S; Ballestar, Esteban; Wculek, Stefanie K; Sancho, David
Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
NOD1 is a key mediator of atrial myopathy in heart failure.
(IVYSPRING INT PUBL, 2026) Gil-Fernández, Marta; Val-Blasco, Almudena; Bueno-Sen, Andrea; Cantolla-Pablo, Paula; Galán-Arriola, Carlos; Ayaon, Ali; López-Fernández, Teresa; Aguilar-Sanchez, Yuriana; Lahiri, Satadru K; Navarro-García, José Alberto; Peinado, Rafael; Aroca, Angel; Rubio, Miguel Ángel; Blázquez, José Antonio; Tamayo, María; López-Collazo, Eduardo; Ruiz-Hurtado, Gema; Jorge, Inmaculada; Vázquez, Jesús; Prieto, Patricia; Smani, Tarik; Ordoñez, Antonio; Filgueiras-Dama, David; Moreno, Raúl; Rivero-Santana, Borja; Nuche, Jorge; Jalife, José; Ibáñez, Borja; Delgado, Carmen; Boscá, Lisardo; Wehrens, Xander H T; Fernández-Velasco, María
Heart failure (HF)-associated atrial myopathy is driven by complex and poorly understood mechanisms. Emerging evidence suggests that innate immune components contribute to atrial remodeling, yet the role of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) receptors remains unclear. NOD1 expression was characterized in atrial myocardium of HF patients (n = 36) and non-failing controls (n = 45) undergoing valve surgery, and in two porcine models of atrial myopathy with divergent ventricular phenotypes: aortic banding (AoB; preserved LVEF) and left atrial infarction (LAI; reduced LVEF). The causal role of NOD1 in atrial remodeling was assessed using genetic ( and pharmacological (ML-130) loss-of-function approaches in a murine transverse aortic constriction (TAC) model, and through selective NOD1 activation with C12-iE-DAP in wild-type, , and -S2814A mice. Proteomic, phosphoproteomic, transcriptomic, and Ca²⁺ imaging analyses were performed across experimental systems. NOD1 was markedly upregulated in atrial myocardium of HF patients and in both porcine models, across divergent ventricular phenotypes and irrespective of documented rhythm status, correlating with structural and functional indices of atrial disease severity. Genetic NOD1 deficiency in TAC mice prevented atrial dysfunction, structural remodeling, activation of profibrotic molecular pathways and Ca²⁺ mishandling. Pharmacological NOD1 inhibition with ML-130 reproduced the protective effects on atrial structural and Ca²⁺ handling. Selective NOD1 activation with C12-iE-DAP induced atrial Ca²⁺ dysregulation through CaMKII-dependent RyR2-Ser2814 hyperphosphorylation, effects that were abrogated by CaMKII inhibition, and absent in -S2814A mice. Human atrial transcriptomic analysis confirmed enrichment of inflammatory, Ca²⁺-signaling, and extracellular matrix remodeling pathways in HF. Increased CaMKII phosphorylation in human atrial myocardium further corroborated the translational relevance of the NOD1-CaMKII-RyR2 axis. These findings identify the NOD1-CaMKII-RyR2 axis as a cardiomyocyte-centered mechanism linking innate immune activation to atrial Ca²⁺ dysregulation and structural remodeling in HF, establishing NOD1 as a molecular indicator of atrial myopathy burden and a mechanism-based therapeutic target.
Inverse correlation between plasma pyrophosphate hydrolysis and early growth of abdominal aortic aneurysm: a pilot study.
(SPRINGER, 2026-01-04) Villa-Bellosta, Ricardo; Lindholt, Jes S; Martin-Ventura, Jose Luis
Abdominal aortic aneurysm (AAA) is often associated with vascular calcification, the calcium-phosphate crystal deposition in the aortic wall, which could impact aneurysm progression and/or stability. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes pyrophosphate-a natural inhibitor of calcification-thereby promoting calcium deposition. This study analyzes phosphatase activity and pyrophosphate dynamics in the plasma of AAA patients, randomly selected from the whole VIVA cohort, including controls (n = 48, aortic diameter in < 30 mm) and small AAA patients (n = 96, aortic diameter 30-55 mm), which were stratified by growth rate (low < 2 mm/year or high > 2 mm/year, n = 48 in each group), initially adjusted by aortic diameter. The phosphatase activity was assessed at physiological (7.4) and optimal (10.5) pH levels. Phosphatase activity was significantly higher in AAA patients at physiological pH, a pattern absent at optimal pH, suggesting disease-specific alterations. Small AAA patients showed notably higher phosphatase activity and pyrophosphate hydrolysis than controls at physiological pH. An inverse correlation was also observed between phosphatase activity and aortic growth rate. KEY MESSAGES: Increased alkaline phosphatase activity was detected in heparin-plasma samples from patients with abdominal aortic aneurysm at physiological pH (7.4), but not under optimal experimental conditions (pH 10.5), suggesting a disease-related effect that may reflect processes occurring in vivo. Concentrations of tissue-nonspecific alkaline phosphatase in heparin-plasma samples remained unchanged, despite increased hydrolysis of pyrophosphate, a key inhibitor of vascular calcification. Pyrophosphate hydrolysis in heparin-plasma samples correlated inversely with aortic growth rate in abdominal aortic aneurysm patients.
Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload.
(OXFORD UNIV PRESS, 2026-01-13) Galán-Arriola, Carlos; Pérez-Camargo, Daniel; Jorge, Inmaculada; Bautista, Víctor; Ayaon-Albarrán, Ali; Pérez-Martínez, Claudia; de Molina-Iracheta, Antonio; Cádiz, Laura; Medina-Hernández, Danielle; Caballero-Henares, Carlos; Lopez-Martín, Gonzalo J; Vázquez, Jesús; Ochala, Julien; Fuster, Valentin; Sánchez-González, Javier; Ibáñez, Borja
Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets. Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance. LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress. LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.
Administration of Single or Repeated Doses of CDCs in a Swine Model of Reperfused Myocardial Infarction: Magnetic Resonance and Proteomics Evaluation.
(MDPI, 2025-11-22) de Pedro, María Ángeles; Báez-Díaz, Claudia; Jorge, Inmaculada; Vázquez-Lopez, Fátima; Torrescusa-Bermejo, Axiel; Martinez-Fernandez, Beatriz; Pulido, María; López, Esther; Vázquez, Jesús; Sánchez-Margallo, Francisco M; Crisostomo, Veronica
Some studies report better outcomes in cell therapy for myocardial infarction (MI) with repeated administrations. We aimed to elucidate the potential differences in terms of cardiac function and protein expression after one or three doses of cardiosphere-derived cells (CDCs) in a porcine MI model. CDCs were isolated from swine cardiac explants, cultured in cardiomyocyte growth medium (CGM), and prepared for administration. Pigs surviving a 90 min balloon occlusion of the mid-left anterior descending coronary artery (LAD) were randomly allocated to receive vehicle (CON), one (D1), or three (D3) doses of 30 × 10 CDCs via the infarct-related coronary artery. Cardiac function was assessed with magnetic resonance at baseline and 10 weeks. Programmed electrical stimulation to study arrhythmogenicity was performed at 10 weeks. High-throughput quantitative proteomic analysis of infarcted tissue was performed to identify biological processes based on protein abundance changes between groups. No significant differences were found between the three groups for any cardiac function parameter at 10 weeks. No increase in ventricular tachycardia inducibility was seen in treated groups. However, gene ontology and topological analyses revealed potentially beneficial molecular adaptations. Upregulation of GYS1, AGL, and GBE1 indicated an increase in glycogen biosynthesis and energy availability, while an increase in ANK2, along with hub proteins ALB and TRAP1, suggested cardioprotective effects. Furthermore, the increase in remodeling-related proteins, including EPHA4, PODN, and ALPK3, pointed to favorable structural adaptation following infarction. In conclusion, the intracoronary administration of single or repeated doses of 30 × 10 CDCs to a porcine reperfused MI model shows only slight differential improvement in both cardiac function and protein profile in this experimental setting, thus presenting limited translational potential.
Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
(NATURE PORTFOLIO, 2025-12) Ramírez-Pardo, Ignacio; Campanario, Silvia; Chavda, Bhakti; Santiago-Fernández, Olaya; Flández, Marta; Grima-Terrén, Mercedes; Cisneros, Andrés; Calls-Cobos, Aina; Itzhak, Daniel N; Ngo, Bryan; Janaki-Raman, Sudha; Kantz, Edward D; Ortet, Laura; Diaz, Antonio; Lindenau, Kristen; Doménech-Fernández, Julio; Gómez-Cabrera, Mari Carmen; Camafeita, Emilio; Vázquez, Jesús; Martinez-Vicente, Marta; Serrano, Antonio L; Perdiguero, Eusebio; Isern, Joan; Cuervo, Ana Maria; Muñoz-Cánoves, Pura
Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
Pro-regenerative fingerprints identified in a sub-population of adult mouse cardiomyocytes by integrative single-cell proteomics.
(BioMed Central, 2026-05-22) Marín-Vicente, Consuelo; Villa Del Campo, Cristina; Calvo, Enrique; Rodríguez, Jose Manuel; Sierra, Rocío; Martín-Salamanca, Sandra; Torroja, Carlos; Végvári, Akos; Zubarev, Roman A; Torres, Miguel; Vázquez, Jesús
Recent advances in instrument sensitivity and sample preparation techniques are significantly improving the ability to study the heterogeneity of cell populations at the single-cell level by mass spectrometry-based proteomics. Integrating multiple layers of cellular data offers additional and yet unexplored insights in single-cell proteomics. In regenerative research, cardiomyocyte proliferation driven by the overexpression of the Myc transcription factor has been described, however, it has not yet been investigated at single-cell resolution. By using an optimized adult cardiomyocytes isolation procedure from mouse models and taking advantage of the integrative capabilities of the iSanXoT application, we are able to minimize batch effects and cell size-related biases, obtain quantitative subcellular compartment information and detect protein alterations within subcellular compartments, as it had not yet been defined for this methodology. This approach enhances data quantification accuracy and facilitates biological interpretation. We show that the Myc transcription factor switches the expression profile of metabolic enzymes and expands a subpopulation of adult cardiomyocytes with a pro-regenerative signature. We demonstrate that different layers of information can properly pattern the proteomic phenotype of single-cells. The analysis of single-cardiomyocyte data with the integrative statistical framework of iSanXoT provided important clues to understand the impact of Myc transcription factor in provoking different immaturity and pro-regenerative signatures in adult mouse cardiomyocytes. The cellular heterogeneity exerted by mouse cardiomyocytes upon Myc overexpression demonstrates the relevance of conducting regenerative studies at the single-cell level for precisely defining the amplitude of this response in the heart.
Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
(NATL ACAD SCIENCES, 2026-04-07) García-Domínguez, Esther; García-Domínguez, Cristina; Cabrera-Alarcón, José Luis; Muñoz-Hernández, María Del Mar; Hernansanz-Agustín, Pablo; Curtabbi, Andrea; Domenech-Fernandez, Julio; Calvo, Enrique; Vázquez, Jesús; Serrano, Antonio L; Muñoz-Cánoves, Pura; Olaso-González, Gloria; Enríquez, José Antonio; Gómez-Cabrera, María Carmen
Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes.
(WILEY, 2026-03) Bou-Teen, Diana; Valiuska, Simonas; Miro-Casas, Elisabet; Rubeo, Chiara; Bonzon-Kulichenko, Elena; Nichtova, Zuzana; Fernandez-Sanz, Celia; Inserte, Javier; Rodriguez-Sinovas, Antonio; Benito, Begoña; Ródenas-Alesina, Eduard; Vázquez, Jesús; Ferreira-González, Ignacio; Ruiz-Meana, Marisol
Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.
Fibronectin-induced overactivation of αβ-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
(NATURE PORTFOLIO, 2026-07-06) Alarcón-Ruiz, Iván; Ruiz-Rodríguez, María Jesús; Martínez-Martínez, Sara; Toral, Marta; Martín-Bermejo, Noelia; Mateos-García, Sergio; Gil-Ruiz, Teresa; Herrero-Galán, Elías; Méndez-Olivares, María José; López-Maderuelo, Dolores; Gutiérrez-Martínez, Carolina; Clemente, Cristina; Clemente-Manteca, Alejandro; H-Alcántara, Alberto; Guala, Andrea; Evangelista, Arturo; Teixido-Tura, Gisela; Rodríguez-Puyol, Diego; Nistal, Juan Francisco; Alegre-Cebollada, Jorge; Vázquez, Jesús; Duarte, Juan; Redondo, Juan Miguel; Campanero, Miguel R
Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αβ-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αβ integrin and ILK expression. Disrupting FN assembly or inhibiting αβ, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αβ-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.
Mitochondria directly interact with the nuclear pore complex.
(NATURE PORTFOLIO, 2026-06) Menendez-Montes, Ivan; Marin-Vicente, Consuelo; Mukherjee, Shibani; Ahmed, Mahmoud Salama; Gomez, Manuel Jose; Anene-Nzelu, Chukwuemeka George; Lee, Chang Jie Mick; Koslowski, Svenja; Solmonson, Ashley; Tassin, Tara; Ali, Shah R; Pessoa, Pedro; Elnwasany, Abdallah; Lam, Nicholas T; Thet, Suwannee; Calvo, Enrique; Cardoso, Alisson C; Pereira, Ana Helena M; Xiao, Feng; Wang, Ping; Mohamed, Asim; El-Feky, Hamed; Elghamry, Ahmed; Gancedo-Alonso, Gonzalo; Nguyen, Ngoc Uyen Nhi; Hsu, Ching-Cheng; Westfall, Aundrea K; DeBerardinis, Ralph; Foo, Roger Sik-Yin; Kinter, Michael; Pressé, Steve; Xing, Chao; Szweda, Luke; Aroumougame, Asaithamby; Sanchez-Cabo, Fatima; Enriquez, Jose Antonio; Torres, Miguel; Vazquez, Jesus; Sadek, Hesham A
Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes, which control pathways including redox and calcium homeostasis. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
Fibroblast Growth Factor 23 as a Prognostic Biomarker in Post-Myocardial Infarction Outcomes: Influence of Renal Function and Its Modulation by Klotho.
(WILEY, 2026-02-17) Vázquez-Sánchez, Sara; Blasco, Ana; Polo-Salguero, Marina; Mourino-Álvarez, Laura; Gil-Fernández, Marta; Corbacho-Alonso, Nerea; Navarro-García, José Alberto; Mercado-García, Elisa; González-Lafuente, Laura; Rodríguez-Sánchez, Elena; González-Moreno, Daniel; Pérez-Gómez, Alberto; Matutano, Andrea; Vázquez, Jesús; López, Juan Antonio; Fernández-Velasco, María; Barderas, María G; Ruiz-Hurtado, Gema
Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.
Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.
(OXFORD UNIV PRESS, 2022-12-29) González-Amor, María; García-Redondo, Ana B; Jorge, Inmaculada; Zalba, Guillermo; Becares, Martina; Ruiz-Rodríguez, María J; Rodríguez, Cristina; Bermeo, Hugo; Rodrigues-Díez, Raquel; Rios, Francisco J; Montezano, Augusto C; Martínez-González, Jose; Vázquez, Jesús; Redondo, Juan Miguel; Touyz, Rhian M; Guerra, Susana; Salaices, Mercedes; Briones, Ana M
Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.
Early renal and vascular damage within the normoalbuminuria condition.
(LIPPINCOTT WILLIAMS & WILKINS, 2021-11-01) Santiago-Hernandez, Aranzazu; Martin-Lorenzo, Marta; Martínez, Paula J; Gómez-Serrano, María; Lopez, Juan Antonio; Cannata, Pablo; Esteban, Vanesa; Heredero, Angeles; Aldamiz-Echevarria, Gonzalo; Vázquez, Jesús; Ruiz-Hurtado, Gema; Barderas, Maria G; Segura, Julian; Ruilope, Luis M; Alvarez-Llamas, Gloria
A continuous association between albuminuria and cardiorenal risk exists further below moderately increased albuminuria ranges. If only based in albumin to creatinine ratio (ACR) higher than 30 mg/g, a significant percentage of individuals may be out of the scope for therapeutic management. Despite epidemiological outcomes, the identification of biochemical changes linked to early albuminuria is underexplored, and normoalbuminuric individuals are usually considered at no risk in clinical practice. Here, we aimed to identify early molecular alterations behind albuminuria development. Hypertensive patients under renin-angiotensin system (RAS) suppression were classified as control, (ACR < 10 mg/g) or high-normal (ACR = 10-30 mg/g). Urinary protein alterations were quantified and confirmed by untargeted and targeted mass spectrometry. Coordinated protein responses with biological significance in albuminuria development were investigated. Immunohistochemistry assays were performed in human kidney and arterial tissue to in situ evaluate the associated damage. A total of 2663 identified proteins reflect inflammation, immune response, ion transport and lipids metabolism (P value ≤ 0.01). A1AT, VTDB and KNG1 varied in high-normal individuals (P value < 0.05), correlated with ACR and associated with the high-normal condition (odds ratio of 20.76, 6.00 and 7.04 were found, respectively (P value < 0.001)). After 12 months, protein variations persist and aggravate in progressors to moderately increased albuminuria. At tissue level, differential protein expression was found in kidney from individuals with moderately increased albuminuria and atherosclerotic aortas for the three proteins, confirming their capacity to reflect subclinical organ damage. Early renal and vascular damage is molecularly evidenced within the normoalbuminuria condition.
Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.
(EDICIONES DOYMA, 2021-02) López-Sainz, Ángela; Hernandez-Hernandez, Aitor; Gonzalez-Lopez, Esther; Domínguez, Fernando; Restrepo-Cordoba, Maria Alejandra; Cobo-Marcos, Marta; Gómez-Bueno, Manuel; Hernandez-Perez, Francisco Jose; Oteo, Juan Francisco; Mirelis, Jesus G; Cavero, Miguel Angel; Moñivas, Vanessa; Mingo Santos, Susana; de Haro-Del Moral, F Javier; Krsnik, Isabel; Salas, Clara; Bornstein, Belén; Briceño, Ana; López, Juan Antonio; Vázquez, Jesús; Alonso-Pulpón, Luis; Segovia, Javier; Garcia-Pavia, Pablo
Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats.
(MDPI, 2021-09-27) Bárcena, Brenda; Salamanca, Aurora; Pintado, Cristina; Mazuecos, Lorena; Villar, Margarita; Moltó, Eduardo; Bonzón-Kulichenko, Elena; Vázquez, Jesús; Andrés, Antonio; Gallardo, Nilda
Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (, , and ) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.
Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.
(NATURE PORTFOLIO, 2021-05-11) de la Fuente-Alonso, Andrea; Toral, Marta; Alfayate, Alvaro; Ruiz-Rodríguez, María Jesús; Bonzón-Kulichenko, Elena; Teixido-Tura, Gisela; Martínez-Martínez, Sara; Méndez-Olivares, María José; López-Maderuelo, Dolores; González-Valdés, Ileana; Garcia-Izquierdo, Eusebio; Mingo, Susana; Martín, Carlos E; Muiño-Mosquera, Laura; De Backer, Julie; Nistal, J Francisco; Forteza, Alberto; Evangelista, Arturo; Vázquez, Jesús; Campanero, Miguel R; Redondo, Juan Miguel
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Titin cleavage in living cardiomyocytes induces sarcomere disassembly but does not trigger cell proliferation.
(Elsevier, 2026-05-15) Pricolo, Maria Rosaria; López-Unzu, Miguel A; Vicente, Natalia; Morales-López, Cristina; Huerta-López, Carla; Pérez-Franco, Wendy; Dumitru, Andra C; Peña-Peña, Jorge; Espinosa, Francisco M; Sanchez, Mateo I; Garcia, Ricardo; Silva-Rojas, Roberto; Torres, Miguel; Herrero-Galán, Elías; Alegre-Cebollada, Jorge
Adult mammalian hearts have limited regenerative capacity due to the inability of cardiomyocytes to proliferate, a major clinical hurdle in contemporary cardiology. The presence of highly organized, contractile sarcomeres has long been considered an impediment for cardiomyocyte division. Indeed, sarcomere disassembly is a crucial step to complete the cell cycle in the few situations where cardiomyocytes have been observed to proliferate. However, whether sarcomere disassembly can per se trigger cell cycle re-entry remains unknown, a possibility that we have tested here. In this study, we have engineered a system to induce sarcomere disassembly in living murine cardiomyocytes based on the specific cleavage of the structural protein titin by tobacco etch virus protease. Although isolated neonatal cardiomyocytes with disassembled sarcomeres remain viable and retain low-amplitude contractile activity, our results show no evidence of increased cardiomyocyte proliferation in targeted cells, as indicated by the analyses of markers of DNA synthesis and cytokinesis. We obtain equivalent results when titin is cleaved in cardiomyocytes stimulated with mitogenic factors in vitro and in the adult myocardium in vivo. These findings suggest that the removal of sarcomere structural barriers is necessary, but not sufficient, for cardiomyocyte proliferation, which implies that additional factors are required for cardiomyocytes to undergo cell division.
Best Paper of the Year 2024.
(SPRINGER, 2025-02) Mukherjee, Rupak; Lara-Pezzi, Enrique

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