Biology subjects

Schmidt, L.

Publications and source records attributed to Schmidt, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Gut Microbiota Fuel Aging Induced by Mitochondrial Dysfunction

Aging is characterized by hallmarks whose mechanistic interdependencies remain poorly defined. Here, we investigate the bi-directional communication between gut microbiota and host mitochondria in the context of immune regulation, healthspan and lifespan. Using a mitochondrial dysfunction PolgAmut mouse model of accelerated aging, we tested the role of mitochondrial dysfunction in modulating microbial homeostasis and aging. We find that impairment of mitochondrial function hastens the decline of microbiota structure over time and induces immune dysregulation and inflammation through metabolic reprogramming of the myeloid immune subset. Further, we find that gut microbiota drives a paradoxical energy state by reducing mitochondrial function systemically while simultaneously driving energy-intensive programs including immune remodelling and protein synthesis, through mTOR signaling. Thus, aging emerges from the progressive imbalance between microbiota-driven energetic demand and declining mitochondrial energy supply. We postulate that microbiota promote host early-life fitness, at the cost of amplifying metabolic stress and inflammation later in life.

microbiology↗

bioRxiv2026

Mapping the human sperm proteome across compartments, donors and individual cells

The human spermatozoon is among the most specialized cells in the body, yet where its proteins reside, where they come from and how they vary between and within men remain largely unresolved. Here we present the deepest proteomic atlas of human spermatozoa to date, identifying 10,828 proteins across six donors. Abundances correlate well between individuals and are anchored by a conserved core of mitochondrial energy-metabolism proteins, while a smaller fraction varies between donations from the same man. By mechanically separating heads from tails, we assigned thousands of previously unlocalized proteins to a compartment, and by comparing seminal fluid from vasectomized and non-vasectomized men we distinguished sperm- and epididymis-derived proteins from accessory-gland secretions. Using a single-cell analysis workflow we further show that the proteomes of individual spermatozoa can be measured, recovering up to ~1,000 protein groups per cell. In a cohort with total fertilization failure, we find recurrent mitochondrial rather than sperm-egg fusion dysregulation. Together or data provides novel insights into the dynamics of the sperm proteome and male infertility.

cell biology↗

bioRxiv2026

TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Xp11.2 translocation RCC [Xp11.2 tRCC]) is an underdiagnosed and aggressive subtype of RCC with few specific or targeted therapies. The transmembrane glycoprotein CD44 is an emerging target in many advanced malignancies, and with its ligand OPN (SPP1), is a crucial driver of cancer progression, stemness, metastasis, and immune suppression. Here we show that common TFE3-fusions [ including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3] are associated with upregulated expression of CD44 and SPP1, as observed in multiple human and murine bulk transcriptomic studies and a murine tRCC snRNA-Seq dataset. CD44 and/or SPP1 protein expression were also upregulated in murine models of transgenic tRCC kidneys and urine specimens, patient-derived cell lines and human tRCC cases, by immunoblotting and/or IHC. Transient deletion of CD44 was associated with profound and specific suppression of tRCC cell line growth, with decreased mTOR signaling. These data suggest that CD44 and/or SPP1 may potentially drive tumorigenesis in tRCC.

cancer biology↗

bioRxiv2026

Combination of enhanced gene activation and cell death causes lethal inflammatory pulmonary fibrosis

The current paradigm of inflammatory disease etiology is that it is caused by an aberrant increase in either gene activation or cell death. Studying the linear ubiquitin (linUb) chain assembly complex (LUBAC) was instrumental in proving that immune-receptor-dependent cell death can cause inflammatory disease. As LUBAC regulates both, gene activation and cell death, it can, however, also serve to evaluate the inflammatory-disease-initiating role of gene activation. Investigating mice with two different gene-activation-enhancing point mutations in LUBAC components showed that aberrantly increased gene activation in Hoil 1C458A/C458A mice did not cause pathology. In contrast, in HoipN101A/N101A mice it led to untoward cell death which, unexpectedly, was required for pathological inflammation, culminating in lethal lung fibrosis resembling human idiopathic pulmonary fibrosis (IPF). Hence, we here uncover a new etiology of inflammation, whereby aberrantly enhanced gene activation can be root cause of pathological, fibrogenic inflammation, yet intriguingly via inducing untoward cell death.

cell biology↗

bioRxiv2026

When adiposity and listening to reasons for behavioral change make food choices healthier: Behavioral and neural mediators of weight status effects on dietary decision-making following behavioral change interventions.

Resolving the inner conflict between improving eating habits (change talk) and sticking to unhealthy ones (sustain talk) is a key target in communication-based behavioral change interventions such as motivational interviewing (MI). Recent work has shown that this inner conflict affects how tastiness and healthiness are traded off in dietary decision-making. The effect varied with body mass index (BMI). Here we aimed to identify why participants with higher BMI shifted toward healthier food choices after listening to change talk. An evidence accumulation model found that BMI affected health evidence sampling when listening to change talk, and taste evidence sampling when listening to sustain talk. A serial mediation analysis showed that the effect of BMI on change-talk-induced health evidence sampling was explained by stronger resting-state connectivity in the ventromedial prefrontal cortex within the default mode network (DMN), which in turn predicted greater motivation to change eating habits. These cross-sectional findings indicate that the intrinsic functional organization of valuation-related regions within the DMN is associated with motivation to change. They provide evidence that these neural and behavioral factors need to align with contextual cues, such as weight status (as reflected by BMI), and with reasons for behavioral change to promote healthier decision-making.

neuroscience↗

bioRxiv2026

miR-378a Controls Cardiomyocyte Metabolism and Angiogenic Signaling

AimsWhile the muscle-enriched microRNA-378a (miR-378a) has been implicated in cardiac hypertrophy and stress responses, its role in maintaining cardiomyocyte metabolic homeostasis, mitochondrial function, and angiogenic paracrine signaling under physiological and post-injury conditions remains unclear. This study addresses these gaps by examining the molecular and functional consequences of miR-378a deficiency in murine heart and human cardiomyocytes. Methods and ResultsCardiac structure and function were analyzed in miR-378a-deficient (miR-378a-/-) and wild-type (miR-378a+/+) mice at 12 weeks and 17 months of age, revealing that miR-378a loss promoted myocardial fibrosis, altered IGF1R-AKT signaling, and impaired cardiac performance, with age-dependent effects. Integrated transcriptomic and proteomic analyses in miR-378a-/- and control mice, as well as in human iPSC-derived cardiomyocytes (hiPSC-CM) of both genotypes, revealed deregulated pathways related to translation, metabolism, and cardiomyopathy-associated signaling. In hiPSC-CM, miR-378a knockout (KO) impaired mitochondrial respiration, disrupted mitochondrial morphology, and reduced mitochondrial DNA content, accompanied by altered mitophagy and biogenesis. KO cells also showed increased glucose uptake but reduced glycogen storage, accompanied by changes in key metabolic regulators, and displayed diminished angiogenic potential. Finally, hiPSC-CM overexpressing miR-378a were delivered in a mouse model of acute myocardial infarction, but overexpression did not further enhance their therapeutic effect. ConclusionsThis study broadens our understanding of miR-378as physiological role in murine hearts and human cardiomyocytes, demonstrating its impact on contractility, mitochondrial integrity, glucose metabolism, and angiogenic paracrine signaling. However, overexpression of miR-378a in hiPSC-CM offers limited additional benefit in cell therapy for acute myocardial infarction.

cell biology↗

bioRxiv2026

Multimodal fertility cues in chimpanzees: How body odours complement sexual swellings

To attract mating partners, female mammals communicate their reproductive status through one or multiple sensory modalities, providing redundant or complementary information. Chimpanzees (Pan troglodytes) are an excellent model for studying multimodal communication. Exaggerated sexual swellings of females serve as a visual proxy for ovulation but increased male mating interest during maximum swelling suggests that olfactory cues may pinpoint fertility more accurately than the swelling alone. Here, we combined gas chromatography-mass spectrometry, hormonal analyses, and bioassays to examine (1) whether chemical composition of female anogenital odours changes during the fertile period, and (2) whether males are able to detect these changes. Our results suggest that, in addition to prominent olfactory changes associated with swelling stages, chemical cues provide complementary information regarding the timing of the fertile window. These changes, however, are minor compared to those related to swelling stages. Male behavioural responsiveness in bioassays was too low to draw conclusions regarding their ability to detect these subtle shifts when presented with a chemical cue only. Overall, our findings support the existence of a multimodal fertility cue in chimpanzees, wherein visual signals are complemented by subtle olfactory changes indicating the timing of the fertile period.

animal behavior and cognition↗

bioRxiv2026

Mapping corpus callosum architecture: developmental, genetic, and cognitive correlates in youth

The corpus callosum (CC), the largest interhemispheric white-matter tract, plays a central role in higher-order cognitive functions and is frequently altered in neurodevelopmental and psychiatric conditions. However, most diffusion MRI studies rely on tract-averaged measures, which obscure spatially specific microstructural variation along the tract that may hold biologically and functionally meaningful information. This study aimed to provide a fine-grained characterisation of spatial variation in callosal structure and to determine its developmental, genetic, and cognitive correlates. This study leveraged multimodal data from the Philadelphia Neurodevelopmental Cohort (PNC), comprising 1342 participants aged 8-21 years. Diffusion MRI and tractography-based segmentation were used to extract fine-grained spatial variation in diffusion metrics along seven callosal tracts. A candidate gene approach targeted four genes (DCC, CDH2, AKT3, and GLI3) previously linked to the neurobiological mechanisms underlying CC formation. Five cognitive factors were derived from the Penn Computerized Neurocognitive Battery using factor analysis. A two-stage functional data analysis approach to examine global and local associations between along-tract diffusion metrics and age, candidate genetic variants, and behavioural outcomes. Results revealed distinct midline-to-cortical variations of age-related diffusion metrics change across callosal subdivisions. Frontal and parietal heteromodal callosal pathways showed pronounced distal-segment maturation (F = 13 - 23, p [≤] 2.8x10e-16), whereas posterior sensorimotor and occipital callosal tracts exhibited more stable age associations along their lengths (F = 4.2 - 4.3, p = 10e-3). Genetic variations in callosal axon-guidance genes (ROBO1, IQCJ-SCHIP1, NRP1 and DCC) were associated with spatial variation in callosal diffusion metrics, particularly in anterior (rostrum) and posterior callosal subdivisions (isthmus and splenium) (F = 4.29 - 18.61, p-values = 2.2e-16 - 1.4e-04). These regions correspond to early-forming callosal compartments, suggesting that prenatal axon- guidance mechanisms leave enduring spatial patterns on callosal organisation. Finally, spatial variation in callosal microstructure was significantly associated with behavioural performance (F = 2.9 - 21.3, P = 2.8x10e-16 - 0.04), with the strongest and most spatially heterogeneous effects observed for complex cognition and executive functioning. Across all analyses, functional data models generally outperformed tract-averaged linear models, supporting the value of explicitly preserving spatial variation along callosal tracts. Our findings converge on the CC as a spatially differentiated structure in which early genetic modulators and developmental constraints shape region- and segment-specific microstructural architecture that is behaviourally relevant through childhood and adolescence.

neuroscience↗

bioRxiv2026

Human-supervised Agentic AI for Hypothesis Generation and Experimental Assistance in Drug Repurposing

Computational drug repurposing has largely been focused on rapid hypothesis generation, yet real-world applications span a far broader lifecycle, from drug candidate suggestion to designing experiments, analyzing assay data, and iteratively refining candidates. Here, we demonstrate that agentic AI can operate throughout this lifecycle. To this end, we developed RepurAgent, a hierarchical multi-agent AI system comprising a supervisor agent and a planning agent that coordinate four specialized sub-agents (research, prediction, data, and report), through a human-in-the-loop design, with episodic memory and retrieval-augmented generation. The system is grounded in data, tools, and standard operating procedures specific for drug repurposing, developed within the REMEDi4ALL consortium. We validated the agentic system across three scenarios spanning the various stages within the repurposing lifecycle: in Acute Myeloid Leukemia, a blinded expert evaluation indicated that RepurAgent produced substantially more novel and mechanistically credible candidates compared to a vanilla LLM baseline; in a retrospective COVID-19 antiviral screen, RepurAgent acted as an adaptive experimental collaborator, prioritizing compounds with AUC-ROC up to 0.99 without predefined thresholds and flagging confounders missed in manual review; and for Multiple Sulfatase Deficiency, it prioritized 81 high-confidence candidates from 5000 compounds, which were further corroborated by domain experts. These results demonstrate that agentic AI can support across the drug repurposing lifecycle, from hypothesis generation to experimental analysis. RepurAgent is open source and deployed at https://repuragent.serve.scilifelab.se/.

bioinformatics↗

bioRxiv2026

Sodium Ions Regulate GPCR Activation by Remodeling Allosteric Coupling Networks and Hydration Patterns

Sodium ions (Na+) are key modulators of G-protein coupled receptor (GPCR) function, yet their mechanistic role remains incompletely understood. Here, we reveal a novel mode of Na+-mediated inactivation in the dopamine D2 receptor (DRD2), where Na+ reshapes long-range allosteric coupling networks and disrupts a continuous internal water column essential for activation. Using extensive molecular dynamics simulations and alchemical free energy calculations, we show that Na+ induces inactive-like residue interactions in the active state and triggers the formation of a distinct hydration gap. We also identify previously unreported Na+ binding sites and quantify their impact on the active-inactive state equilibrium by thermodynamic scanning. These findings provide mechanistic insights into Na+-driven allosteric regulation of GPCRs and highlight new opportunities for drug design targeting ion-sensitive receptor states. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/714850v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@db861forg.highwire.dtl.DTLVardef@42722dorg.highwire.dtl.DTLVardef@561bc7org.highwire.dtl.DTLVardef@139c9e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Insulin-independent glucose uptake in skeletal muscle by coupled SGLT and Na,K-ATPase transport

Exercise is a cornerstone therapy for diabetes because working skeletal muscles take up glucose at dramatically greater rates than postprandial insulin-stimulated glucose uptake and, notably, do so without a requirement for insulin. This remarkable ability of working muscles is preserved in diabetes, when muscles become resistant to insulin. However, the mechanism of insulin-independent glucose uptake by working muscles is not fully understood. Here we describe a previously unrecognized glucose uptake pathway in muscle, which we refer to as "mSGLT" based on shared properties with the Sodium Glucose Linked Transporter family. In contrast to the abundant GLUT4 transporter, mSGLT is not regulated by insulin, requires Na,K-ATPase-2 activity, and transports the hexose -methyl-D-glucoside (MDG), a glucose derivative that is handled by SGLTs but not GLUT4. The mSGLT pathway and GLUT transport pathways are independent and additive. In addition to exercise, mSGLT imports glucose under other conditions of adrenergic stimulation, which inhibits pancreatic insulin release and reduces the insulin sensitivity of muscle. SGLT2-specific antibodies recognize a protein in muscle of similar size to the kidney SGLT2; this protein localizes to the muscle t-tubules, together with Na,K-ATPase-2 and MAP17, the regulatory subunit of SGLT2. However, skeletal muscles do not express a full-length transcript of Slc5a2 (SGLT2), and SGLT2-specific inhibitors do not inhibit mSGLT with high affinity. The novel transporter may be a muscle variant of Slc5a2 that results from post-transcriptional or post-translational mechanisms. mSGLT and its regulation offer potential muscle-specific therapeutic targets for treating hyperglycemia and other conditions when insulin-stimulated glucose disposal into muscle is impaired.

physiology↗

bioRxiv2026

Oncodevelopmental plasticity of the skeleton in myeloid neoplasms

Myelofibrosis in patients with myeloproliferative neoplasms (MPNs) is traditionally characterized by bone marrow fibrosis and osteosclerosis, with de novo bone formation commonly attributed to impaired osteoclast-mediated resorption. Here, we challenge this paradigm by demonstrating that a solitary clonal driver mutation simultaneously induces pathological bone formation and resorption, with osteosclerosis acting to conceal localized and active bone destruction rather than inhibiting it. Through population analysis; clinical imaging; patient-derived multi-tissue sequencing; murine models and organ-on-a-chip systems, we demonstrate that spatial and ontogeny-dependent remodeling in mesoderm- and neural crest-derived bones is mechanistically interconnected via a previously unidentified osteochondral stromal injury program. Neural crest-derived stromal cells suppress osteogenic programs and undergo injury-induced lineage plasticity with ectopic chondrogenesis, mirroring pathological remodeling in mesoderm-derived growth plate regions. This shared injury response promotes osteoclastogenesis and is mediated by a conserved Thrombospondin 1+ (THBS1+) stromal population that links fibrotic remodeling to bone loss. Combined pharmacological inhibition of THBS1 and JAK signaling reduces myeloproliferation, halts fibrosis progression, and restores two developmentally distinct bones, establishing THBS1 as a unifying therapeutic target in myelofibrosis.

cancer biology↗

bioRxiv2026

NicheSphere reveals Spp1⁺ macrophages as central hubs coordinating fibrotic remodeling in myeloproliferative neoplasms

Bone marrow fibrosis in myeloproliferative neoplasms arises from interactions between mutant hematopoietic clones and fibrosis-driving stromal cells. We identify Spp1 macrophages as central "communication hubs" integrating inflammatory and fibrotic programs via spatial proximity, ECM signaling, and cytokine activation. Using dual lineage-tracing, single-cell and multiplet RNA-sequencing, and a novel computational method for cell-colocalization and communication analysis named NicheSphere, we show that Spp1 macrophages form core communication hubs with osteoCAR cells, fibroblasts, and megakaryocytes. NicheSphere uncovered two distinct niches: macrophage-enriched compartments driving WNT, JAK-STAT, and TNF cytokine signaling, and a fibrosis-interacting core enriched in TGF-{beta} and ECM glycoproteins. Genetic ablation revealed cooperative roles of stromal and hematopoietic Spp1 in sustaining fibrosis and inflammation. Mechanistically, SPP1 promoted integrin-mediated adhesion, IL-1{beta} secretion, and stromal activation, while IL-1 cytokines induced Spp1 and collagen expression. Loss of Spp1 in hematopoietic progenitors reduced inflammation and restored macrophage function, establishing SPP1 macrophages as therapeutic targets in progressive bone marrow fibrosis.

cancer biology↗

bioRxiv2025

Dynamic assessment of the allocation of copper to cytochrome c oxidase using size-exclusion chromatography (SEC) combined with inductively coupled plasma mass spectrometry (ICP-MS)

Copper (Cu) is an essential trace element required for mitochondrial respiration via its incorporation into cytochrome c oxidase (CuCOX), the terminal enzyme of the electron transport chain. In this study, we employed size-exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS), UV-Vis spectroscopy, and immunoblotting to identify and validate a high-molecular-weight Cu-containing peak in SEC-ICP-MS chromatogram as representative of CuCOX activity. We demonstrate that this CuCOX peak is enhanced under metabolic conditions favoring oxidative phosphorylation, such as high Cu supplementation or galactose-containing media, and correlates with increased mitochondrial respiration. By tracing exogenously supplied 63Cu, we characterized the time- and dose-dependent incorporation of newly acquired Cu into CuCOX. Functional RNA interference (RNAi) experiments targeting key Cu transporters revealed that CuCOX formation is independent of the high-affinity Cu importer CTR1, but instead relies on alternative transporters including DMT1, LAT1, and the mitochondrial carrier SLC25A3. These findings offer new insight into the cellular pathways governing Cu trafficking and allocation to mitochondria under physiologically relevant conditions. Furthermore, our work establishes SEC-ICP-MS as a sensitive and specific method for quantifying CuCOX and assessing mitochondrial metabolism. This platform holds promise for the identification of Cu-related biomarkers and therapeutic targets, particularly in the context of diseases such as renal cell carcinoma (RCC), where dysregulated Cu homeostasis plays a critical role.

biochemistry↗

bioRxiv2024

A structural MRI marker predicts individual differences in impulsivity and classifies patients with behavioral-variant frontotemporal dementia from matched controls

Impulsive decision-making is a symptom across many neuropsychiatric and neurological disorders. Yet, it is still unknown whether impulsivity can be predicted based on individual differences in brain structure. Here, we used machine-learning to develop a structural MRI signature of impulsivity, tested its validity in several independent samples, and assessed its diagnostic value in patients with behavioral variant frontotemporal dementia (bvFTD)--a neurodegenerative disease characterized by high impulsivity. The resulting whole-brain grey matter density pattern--the Structural Impulsivity Signature (SIS)--showed a good prediction-outcome correlation of r=0.35 (out-of-sample, p=0.0028) in the training sample of healthy adults (N=117) and significantly predicted individual differences in impulsivity in four other, independent studies (total N=626), including healthy and clinical participants with neuropsychiatric and neurological conditions. Further, the SIS separated bvFTD patients from controls with high accuracy (81% correct, p=0.002) and predicted impulsivity-related symptom severity among patients. The spatial distribution of weights in the SIS brain pattern highlights the key role of brain regions associated with affective processing in impulsivity. Together, these results provide evidence for a new structural neuromarker of individual differences in impulsivity that can be easily applied to new samples. Future studies can further assess its predictive value towards better prevention, diagnosis and treatment of mental disorders associated with impulsivity symptoms.

neuroscience↗

bioRxiv2024

Simulating a medical expertise: a robust novel stress induction paradigm in chronic pain patients

Maladaptive stress responses may exacerbate chronic widespread pain (CWP) and deserve further investigations. Yet, existing stress induction paradigms lack relevance for individuals with this condition. Hence, we developed the Social Benefits Stress Test (SBST), adapted from the Trier Social Stress Test. Instead of a job interview, the main task consists in justifying the inability to work. Forty women with CWP in the context of hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorders were included. They underwent a 30-min baseline, the new stress task and a recovery period. The psychophysiological stress response was captured using self-reported stress ratings, salivary cortisol and - amylase levels, as well as continuous physiological monitoring of heart rate variability (HRV) and electrodermal activity (EDA). Compared to baseline, the analysis revealed a significant and transient increase in stress ratings during the stress task, associated with a peak in salivary biomarkers concentrations. The HRV signal analysis showed a significant decrease in high frequency power (HF), and increases in heart rate, low frequency power (LF) and in LF/HF ratio. The EDA analysis revealed a significant increase in skin conductance level (SCL) tonic component and skin conductance response (SCR). Subjective stress ratings positively correlated with changes in salivary biomarkers, LF/HF ratio and EDA outcomes. The SBST induced a reproducible moderate stress response across subjective and physiological measures in a population of CWP patients, validating this task as a relevant experimental model of social stress in chronic pain. The SBST is a useful tool to study the relationship between stress and chronic pain. PerspectiveThis manuscript presents the Social Benefits Stress Test (SBST) as a novel paradigm to assess stress reactivity in chronic widespread pain patients. By simulating the challenge of justifying work incapacity, it elicits a reproducible stress response, supporting its use as a model to study stress-pain interactions and evaluate therapeutic interventions.

neuroscience↗

bioRxiv2024

High delay discounting relates to core symptoms and to pulvinar atrophy in frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioural changes and atrophy in brain regions important for decision-making. Computations such as trading off between larger later (LL) and smaller sooner (SS) rewards -- called delay discounting in behavioural economics -- might be heavily impaired by bvFTD. In this cross-sectional study, our objectives were to investigate (1) whether bvFTD patients show higher delay discounting than healthy controls, (2) whether this maladaptive discounting correlates with impulsivity-related bvFTD symptoms, and (3) in which brain regions atrophy is related to bvFTDs steeper discounting. BvFTD patients (N=24) and matched controls (N=18) performed two delay discounting tasks: one with monetary rewards and one with food rewards. We compared discount rates (log(k)) in bvFTD patients and controls and tested their correlations with symptoms. We used participants structural MRI data and applied whole-brain mediation analyses to investigate brain structures mediating the effect of bvFTD on delay discounting. For both monetary and food rewards, delay discounting was significantly higher in bvFTD patients than in healthy controls. BvFTD patients higher discounting of both money and food was associated with their greater disinhibition and eating behaviour changes. Whole-brain mediation analyses revealed that (1) several brain regions (left thalamic pulvinar, left parahippocampal cortex, right temporal lobe) were predictive of steeper discounting of both money and food and (2) grey matter density in these brain regions, including most prominently the medial pulvinar, mediated the effect of bvFTD on discounting. The impulsive preference for sooner rewards captured by delay discounting might constitute a common mechanism of the behavioural symptoms of inhibition deficit and eating behaviour changes in bvFTD. Future studies could further investigate the potential role of medial pulvinar structural modifications as a transdiagnostic marker and a therapeutic target of impulsivity troubles.

neuroscience↗

bioRxiv2024

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H2O2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/575895v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@14e1b89org.highwire.dtl.DTLVardef@f1c83forg.highwire.dtl.DTLVardef@191aff8org.highwire.dtl.DTLVardef@1b7ccd1_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIAccumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth. C_LIO_LICu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis. C_LIO_LICu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. C_LIO_LICu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of CuHi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H2O2 Fenton-like reaction mediated cell death. C_LIO_LIProgression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth. C_LI

cancer biology↗