Biology subjects

Pena, S.

Publications and source records attributed to Pena, S..

7 recordsLinked to original sources

bioRxiv2025

Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism

Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo. Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.

physiology↗

bioRxiv2025

Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

cancer biology↗

bioRxiv2025

A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling

Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic {beta}-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role {beta}-cell senescence in diabetes progression. In contrast, {beta}-cell senescence also promotes immune surveillance, promoting {beta}-cell survival and function. Thus, a better understanding of senescent cells phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent {beta}-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21Cip1) and Cdkn2a (encoding p16Ink4a) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent {beta}-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a-expressing {beta}-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a+ cells was sufficient to induce secondary senescence and {beta}-cell dysfunction in vitro. JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored {beta}-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/648438v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@9b8addorg.highwire.dtl.DTLVardef@1b9c4eborg.highwire.dtl.DTLVardef@12f2964org.highwire.dtl.DTLVardef@1468297_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

Mitochondria transported by Kinesin 3 prevent localized calcium spiking to inhibit caspase-dependent specialized cell death

Polarized cells (such as neurons), defined by distinct compartments are, like many cell types, subject to developmental elimination, as in neurite pruning. The molecular mechanism behind specialized elimination remains a largely open question. We previously introduced the "tri-partite" embryonic cell death program Compartmentalized Cell Elimination (CCE) in the scaffolding tail-spike epithelial cell and sex-specific CEM neurons of C. elegans. CCE is stereotyped and ordered, with three distinct programs eliminating three cell compartments, and bearing morphological hallmarks reminiscent of neurite pruning. Here we report first, that, prior to CCE onset, mitochondria undergo UNC-116/Kinesin 1-dependent irreversible retrograde transport; and second, that the caspase protease CED-3 promotes the completion of the proximal nicking event of CCE by helping inhibit the kinesin 3 homolog UNC-104. While known canonically to carry only synaptic vesicles, UNC-104/Kinesin 3, in the CCE context, and in the absence of CED-3/Caspase, can transport mitochondria anterogradely to the severing site. We observe both caspase activity and Ca2+ spiking at this site prior to nicking. Mitochondria appear to protect against nicking in the absence of CED-3 via their MCU-1 uniporter-dependent Ca2+ uptake capacity. Our study sheds light on the molecular machinery of specialized cell elimination and pruning, highlighting involvement of region-specific Ca2+ signaling, an anti-death function of mitochondria via local Ca2+ uptake, mitochondrial transport as a regulatory strategy, with UNC-116/kinesin 1-mediated retrograde transport important for cell elimination priming and UNC-104/kinesin 3 in a previously undescribed role as a non-canonical anterograde mitochondrial motor.

cell biology↗

bioRxiv2023

SHORT-TERM CALORIC RESTRICTION IN MICE PROMOTES RESOLUTION OF ATHEROSCLEROSIS, WHILE WEIGHT REGAIN ACCELERATES ITS PROGRESSION

ABSTRACTWhile weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerotic plaque resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/539777v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@c6e857org.highwire.dtl.DTLVardef@bfd443org.highwire.dtl.DTLVardef@88973org.highwire.dtl.DTLVardef@78198f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Cardiomyocyte transcriptomic signatures in response to Trypanosoma cruzi infection underpin Chagas cardiomyopathy progression.

Chagas disease can lead to life-threatening cardiac manifestations that occur more frequently in geographic areas more prevalent with the TcI/II circulating genetic strains. To elucidate the differential transcriptomic signatures of the cardiomyocyte resulting from infection with TcI/II or TcVI T. cruzi strains and explore their relationships with pathogenesis, HL-1 rodent cardiomyocytes were infected with TcI/II or TcVI T. cruzi trypomastigotes. RNA was isolated serially post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change [≥]2 or [≤] 0.5) highlighted the over-represented biological pathways. We found that Oxidative stress-related GO terms, Hypertrophy model, Apoptosis, and MAPK signaling pathways (all with p<0.01) were upregulated. Glutathione and one-carbon metabolism pathway, and Cellular nitrogen compound metabolic process GO term (all with p <0.001) were upregulated exclusively in the cardiomyocytes infected with the TcI/II strains. Upregulation in the oxidative stress-related and hypertrophic responses are shared hallmarks with viral myocarditis, another inflammatory cardiac pathology. Nitrogen metabolism upregulation and Glutathione metabolism imbalance may implicate the relation of nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of chagasic cardiomyopathy development. ImportanceChagas disease affects more than 6 million people worldwide. One-third of those chronically infected will develop the life-threatening condition Chagas Cardiomyopathy (CCM). Trypanosoma cruzi (T. cruzi), grouped based on their genetic variability into six discrete typing units (DTU), are associated with DTU-specific clinical phenotypes. The diverse genetic make-up of parasite virulence factors shall evoke unique host defense responses of variable magnitude, collectively affecting the phenotypic expression of CCM. To address this, we performed a transcriptome analysis of cardiomyocytes infected with three different T. cruzi strains each belonging to a different DTU. As a result, we were able to point out dysregulation in nitrogen metabolic processes, Glutathione, and one-carbon metabolism pathways as main features in the host response against cardiomyopathy-prone T. cruzi strains. Further research on these pathways could serve not only in the lookout for progression biomarkers but also in the lead toward the discovery of new therapeutic targets.

cell biology↗

bioRxiv2020

Discovery and Predictive Modeling of Urine Microbiome, Metabolite and Cytokine Biomarkers in Hospitalized Patients with Community Acquired Pneumonia

Pneumonia is the leading cause of infectious related death costing 12 billion dollars annually in the United States alone. Despite improvements in clinical care, total mortality remains around 4%, with inpatient mortality reaching 5-10%. For unknown reasons, mortality risk remains high even after hospital discharge and there is a need to identify those patients most at risk. Also of importance, clinical symptoms alone do not distinguish viral from bacterial infection which may delay appropriate treatment and may contribute to short-term and long-term mortality. Biomarkers have the potential to provide point of care diagnosis, identify high-risk patients, and increase our understanding of the biology of disease. However, there have been mixed results on the diagnostic performance of many of the analytes tested to date. Urine represents a largely untapped source for biomarker discovery and is highly accessible. To test this hypothesis, we collected urine from hospitalized patients with community-acquired pneumonia (CAP) and performed a comprehensive screen for urinary tract microbiota signatures, metabolite, and cytokine profiles. CAP patients were diagnosed with influenza or bacterial (S. aureus and S. pneumoniae) etiologies and compared with healthy volunteers. Microbiome signatures showed marked shifts in taxonomic levels in patients with bacterial etiology versus influenza and CAP versus normal. Predictive modeling of 291 microbial and metabolite values achieved a +90% accuracy with LASSO in predicting specific pneumonia etiology. This study demonstrates that urine from patients hospitalized with pneumonia may serve as a reliable and accessible sample to evaluate biomarkers that may diagnose etiology and predict clinical outcomes. Author SummaryUrine has been classically considered sterile since most microorganisms are not readily culturable under healthy circumstances. Further, many pneumonia patients are immediately placed on antibiotics rendering culture-based techniques useless. However, the advent of next generation sequencing has enabled unprecedented analysis of the microbial communities - living or detected as free DNA - found in many niches of the human body. Here, we describe a urine microbiome as well as metabolites and cytokines measured in patients newly admitted to the hospital diagnosed with influenza or bacterial (S. aureus and S. pneumoniae) infection pneumonia, compared with healthy controls. Using these parameters alone, we were able to achieve high success in predicting patient pneumonia. This study provides a proof of concept that urine samples, which are easily accessible in outpatient and inpatient settings, could provide additional diagnostic insights to patient infectious status and future risk factor for complication.

systems biology↗