http://hdl.handle.net/10366/3966 2026-09-17T01:07:31Z http://hdl.handle.net/10366/172707 [EN]The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3-6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions. 2024-07-01T00:00:00Z http://hdl.handle.net/10366/172704 [EN]Cultured brain cells are used conventionally to investigate fundamental neurobiology and identify therapeutic targets against neural diseases. However, standard culture conditions do not simulate the natural cell microenvironment, thus hampering in vivo translational insight. Major weaknesses include atmospheric (21%) O2 tension and lack of intercellular communication, the two factors likely impacting metabolism and signaling. Here, we addressed this issue in mouse neurons and astrocytes in primary culture. We found that the signs of cellular and mitochondrial integrity were optimal when these cells were acclimated to grow in coculture, to emulate intercellular coupling, under physiologic (5%) O2 tension. Transcriptomic scrutiny, performed to elucidate the adaptive mechanism involved, revealed that the vast majority of differentially expressed transcripts were downregulated in both astrocytes and neurons. Gene ontology evaluation unveiled that the largest group of altered transcripts was glycolysis, which was experimentally validated by metabolic flux analyses. This protocol and database resource for neural cells grown under in vivo-like microenvironment may move forward the translation of basic into applied neurobiological research. 2024-12-01T00:00:00Z http://hdl.handle.net/10366/172700 [EN]TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level. 2024-11-18T00:00:00Z http://hdl.handle.net/10366/172698 [EN]Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy. 2025-01-13T00:00:00Z http://hdl.handle.net/10366/172683 [EN]Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis. 2026-01-01T00:00:00Z http://hdl.handle.net/10366/172682 [EN]This editorial challenges the long-held neuron-centered view of brain metabolism, relying on ample evidence that it is a cooperative, multicellular process. Astrocytes, oligodendrocytes, and other glia play active roles providing lactate, antioxidant support, and substrate shuttles that fuel neuronal function and memory. Despite mounting data, some critics persist in refuting intercellular metabolic exchange, often guided more by entrenched creeds than concrete evidence, slowing constructive, hypothesis-driven discourse and delaying clinical and neuroprotective advances. The authors call for a rigorous research agenda: cell-type-specific manipulations, advanced biosensors, imaging and biomarkers, and integration with behavior and electrophysiology. They urge redirecting focus from outdated dogma to physiology-driven exploration of glia-neuron metabolic partnerships. 2025-07-01T00:00:00Z http://hdl.handle.net/10366/172681 (No abstract available) 2025-08-29T00:00:00Z http://hdl.handle.net/10366/172675 [EN]Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron-astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets. 2025-12-01T00:00:00Z http://hdl.handle.net/10366/172672 Astrocytes, the most abundant glial cell type in the central nervous system, have traditionally been viewed from the perspective of metabolic support, particularly supplying neurons with lactate via glycolysis. This view has focused heavily on glucose metabolism as the primary mode of sustaining neuronal function. However, recent research challenges this paradigm by positioning astrocytes as dynamic metabolic hubs that actively engage in lipid metabolism, especially mitochondrial fatty acid β-oxidation. Far from serving solely as an energy source, fatty acid ß-oxidation in astrocytes orchestrates reactive oxygen species-mediated signaling pathways that modulate neuron-glia communication and cognitive outcomes. This review integrates recent advances on astrocytic fatty acid ß-oxidation and ketogenesis, alongside other metabolic pathways converging on reactive oxygen species dynamics, including cholesterol metabolism and peroxisomal β-oxidation. In reframing astrocytic metabolism from energy provision to signaling, we propose new directions for understanding central nervous system function and dysfunction. 2026-02-01T00:00:00Z http://hdl.handle.net/10366/172669 [EN]The lack of a universally accepted definition, a gold-standard assessment tool, and sufficient evidence-based interventions has hindered the integration of frailty into routine clinical practice, particularly outside geriatric medicine. For clinicians, health professionals, policymakers, and aging researchers, a unified framework based on robust evidence has become essential. To provide a consensus on relevant aspects of frailty, including definition, attributes, misunderstandings, pathophysiology, phenotypes, assessment, biomarkers, management, stigmas and future challenges, useful for epidemiological, clinical and research application across Europe. Consensus document. 25 research centers on frailty and healthy aging. Relevant aspects on frailty. In this document we present a consensus regarding what frailty is, what frailty is not, what is aging, which are the most common misunderstandings related to frailty, which is the pathophysiology and which are the biomarkers of frailty, how should frailty be assessed and who should assess frailty, how should frailty be managed, the presence or absence of frailty subphenotypes or subtypes, how is the stigma of been considered frail, which are the gender considerations, and which are the current challenges and future directions. We support that frailty is the expression of an age-associated clinical phenotypic syndrome driven by the biology of aging, life-course environmental exposures, and disease burden. Its physiological basis lies in a heterogeneous decline of functional reserve across organ systems, accompanied by impaired homeostasis and reduced capacity to respond to stressors, ultimately predisposing to adverse health outcomes, mainly disability. We present a consensus document on frailty, useful for epidemiological, clinical and research application across Europe. 2026-03-01T00:00:00Z http://hdl.handle.net/10366/172666 [EN]Cognition and behaviour arise from computations in neural circuits, which can differ in their readiness for recruitment or in the computations and behavioural outputs that they generate. Mitochondria contribute to both circuit properties and their variability by shaping the cellular processes on which circuit function depends. Across neurons and glia, mitochondria provide bioenergetic support, regulate Ca2+ dynamics and reactive oxygen species levels, influence neurotransmitter synthesis and turnover, and sustain quality control programmes that preserve cellular integrity. The capacity of mitochondria to provide this support and their plasticity have been linked to circuit architecture, engagement and adaptation, with implications for learning and memory, reward and reinforcement, state-trait anxiety and motivation. Here we describe two complementary modes of mitochondrial support: a baseline mode, in which mitochondria sustain circuit architecture and physiological properties over long timescales, and an activity-evoked mode, in which local mitochondrial outputs support synaptic transmission and plasticity. Distinguishing these two modes helps to explain how behavioural modulators, including stress hormones, immune activity and metabolic signals, can shape behaviour by altering either baseline mitochondrial control of circuit readiness or activity-evoked mitochondrial support during circuit engagement. 2026-09-01T00:00:00Z http://hdl.handle.net/10366/172662 Adolescent cannabis use produces lasting and sex-specific effects into adulthood, although poorly explained mechanistically. This study links these cannabis-induced effects to sex-dependent changes in phosphorylation of mitochondrial Complex I subunit NDUFS4 during adolescence, identifying mitochondrial pathways as causal mechanisms and potential therapeutic targets to reduce their long-term consequences. 2026-08-27T00:00:00Z http://hdl.handle.net/10366/172152 [EN]Lifestyle factors may influence disability trajectories in multiple sclerosis (MS), yet prospective data linking sustained dietary adherence to objective clinical outcomes remain limited. Homocysteine, a metabolite involved in one-carbon metabolism, represents a biologically plausible mediator between nutrition and neurodegeneration, although its longitudinal clinical relevance in MS is uncertain. This study aimed to investigate whether adherence to a structured dietary intervention is associated with longitudinal changes in plasma homocysteine levels and disability progression in patients with MS over 12 months. In this prospective cohort study, 41 patients with MS were followed for 12 months. Dietary adherence was quantified using a structured follow-up scale (range 2-6). Plasma homocysteine levels and Expanded Disability Status Scale (EDSS) scores were assessed at baseline, 6 months, and 12 months. Associations between adherence, metabolic changes, and EDSS evolution were evaluated using correlation analyses and multivariate linear regression adjusting for age, sex, BMI, baseline EDSS, and treatment line. Baseline mean homocysteine was 10.91 ± 6.94 μmol/L and decreased to 8.24 ± 3.33 μmol/L at 6 months, remaining stable at 8.27 ± 2.42 μmol/L at 12 months. Between-group differences in homocysteine showed a trend toward significance at 12 months (ANOVA p = 0.059). Mean EDSS increased slightly from 1.14 to 1.23 in the overall cohort (p > 0.05). However, EDSS evolution differed according to dietary adherence (ANOVA p = 0.009): low-adherence patients showed a mean EDSS increase (+0.53 ± 0.72), whereas high-adherence patients showed a mean EDSS decrease (-0.56 ± 1.08). Given the low baseline EDSS, short follow-up, and small high-adherence subgroup, these changes should be interpreted as exploratory differences in short-term EDSS trajectory rather than confirmed clinical improvement and do not establish causality. Adherence score was inversely correlated with EDSS change (r = -0.57, p = 0.0006) and remained independently associated in multivariate analysis (β = -0.45, 95% CI -0.68 to -0.22, p = 0.0005). Higher adherence to the dietary counselling programme was associated with a more favourable short-term disability trajectory over 12 months. However, causality cannot be inferred, and the clinical significance of these modest changes remains uncertain. Because the adherence score was not formally validated and may partly reflect broader health-related behaviours or engagement with care, and because the dietary intervention was individualized, the study cannot identify specific dietary components or dietary patterns associated with disability trajectories. These exploratory findings require confirmation in larger controlled studies using validated dietary assessment instruments. 2026-07-07T00:00:00Z http://hdl.handle.net/10366/172029 [EN]Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer’s disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/171830 [EN]Early identification of patients with multiple sclerosis (MS) at risk of transitioning from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) remains a major clinical challenge. Although magnetic resonance imaging (MRI) is widely used to monitor disease activity, imaging markers alone may not adequately predict progression. The identification of accessible biochemical markers associated with disability progression could improve long-term monitoring. This retrospective observational study evaluated clinical, radiological, and biochemical parameters in 45 MS patients followed at a single tertiary center. Twenty-three patients remained in the RRMS phase, while 22 developed SPMS. Cerebrospinal fluid (CSF) biomarkers obtained at diagnosis and serum biomarkers measured at two time points separated by two years were analyzed. Group comparisons used non-parametric tests, and associations with disability were assessed using Spearman correlation. Serum albumin and total protein levels measured two years before progression were significantly lower in patients who later developed SPMS compared with those who remained RRMS. Creatinine and ferritin did not differ between groups. In RRMS patients, ferritin levels decreased significantly over time, whereas albumin and total protein remained stable. CSF IgG index values tended to be higher in patients who later developed SPMS, without reaching statistical significance. MRI activity was not associated with progression. Total serum protein levels were inversely correlated with EDSS scores. Lower serum protein levels may precede clinical transition to SPMS and reflect processes related to disability progression. Despite not being independent predictors, their accessibility supports their potential role in longitudinal monitoring strategies. 2026-07-01T00:00:00Z http://hdl.handle.net/10366/171818 [EN] Plants provide oxygen, food, shelter, medicines and environmental services, without which human society could not exist. Tackling pressing and global challenges requires well-trained plant scientists and plant-aware individuals. This manifesto provides a practical evidence-based vision to strengthen plant science education, focused on five strategic priorities. It is relevant to all stakeholders within plant science and beyond: from frontline educators to institutional leaders; from commercial or charitable professionals to entrepreneurs and donors; from individual community members to their legislative representatives. Strengthening plant science education demands concrete actions from all stakeholders, ultimately to the benefit of us all. 2025-01-01T00:00:00Z