Biology subjects

Hannibal, L.

Publications and source records attributed to Hannibal, L..

6 recordsLinked to original sources

bioRxiv2025

Elucidating a potential role of the infant gut microbiome on the bioavailability of L-tyrosine in phenylketonuria

BackgroundPhenylketonuria (PKU) is an inherited metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency, leading to elevated L-phenylalanine and severe neurological damage if untreated. While phenylalanine-based biomarkers are diagnostic and phenylalanine levels correlate with disease severity, the clinical manifestations of PKU are heterogeneous. ResultsTo identify additional reliable, potentially novel biomarkers, we used germ-free sex-specific, organ-resolved infant whole-body metabolic models (infant-WBMs) to simulate PAH deficiency and predicted elevated L-phenylalanine and its derivatives, alongside reduced L-tyrosine fluxes, as the product of phenylalanine hydroxylation. To test the reliability of these predictions, we combined the infant-WBMs with gut microbiome models from 48 healthy infants. Upon integrating microbiome data, we found that microbial metabolism significantly increased L-tyrosine availability, obscuring its utility as a universal biomarker. In [~]23% of microbiome-PKU models, L-tyrosine fluxes remained low, indicating insufficient microbial compensation. These cases were enriched in Firmicutes and lacked specific Bifidobacterium and Escherichia strains linked to L-tyrosine biosynthesis via the pretyrosine pathway. Shadow price analysis identified microbial species critical for host L-tyrosine metabolism. However, some, such as Bifidobacterium dentium, also contributed to L-phenylalanine synthesis, potentially worsening the PKU phenotype. In contrast, L-phenylalanine, phenylpyruvate, and hydroxyphenylacetic acid remained reliably elevated across all models, validating their diagnostic relevance. ConclusionsOur study demonstrates that microbiome composition can modulate biomarker reliability in PKU, particularly for L-tyrosine. Integrating microbial metabolic models with whole-body physiology enables assessment of biomarker reliability and reveals subpopulations for whom secondary biomarkers or targeted probiotics may be beneficial. This approach offers a powerful framework for refining diagnostics and therapy monitoring in rare metabolic diseases and the development of possible targeted microbiome therapies.

systems biology↗

bioRxiv2025

Oncogenic PTPN11/SHP2 drives immune escape in juvenile myelomonocytic leukemia (JMML) through activation of ectonucleotidase/adenosine signaling

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic/myeloproliferative neoplasm of early childhood driven by RAS pathway mutations. Allogeneic hematopoietic stem cell transplantation (HSCT) is the therapy of choice for most patients. However, relapse rate is high, in patients with adverse features, frequently noted in PTPN11-mutated JMML, or in patients without evidence of graft-versus-host disease (GvHD). Here we set out to understand the mechanisms associated with oncogenic PTPN11 immune escape. Analyzing primary PTPN11-mutated JMML samples and MxCre;Ptpn11D61Y/+ mice, we observed elevated expression of immune checkpoint molecules, including ectonucleotidases CD39 and CD73 - key mediators of the adenosine pathway - on monocytic and granulocytic leukemic cells. Stimulation with GM-CSF, a central mediator of JMML pathogenesis, induced ectonucleotidases expression on granulocytes and monocytes. In contrast, MEK inhibition downstream of Ptpn11D61Y/+ reduced ectonucleotidases expression. Functionally, Ptpn11D61Y/+-mutated myeloid cells suppressed activation and proliferation of wild-type (WT) T lymphocytes, an effect recapitulated by adenosine and reversed by pharmacological CD39 inhibition with POM-1. In vivo, POM-1 treatment of MxCre;Ptpn11D61Y/+mice presenting with myeloproliferation reduced spleen size and partially restored immune responsiveness. Moreover, POM-1 induced apoptosis in murine Ptpn11D61Y/+ myeloid cells, highlighting a dual therapeutic benefit of CD39 inhibition in JMML. Together, these findings suggest that targeting the adenosine pathway may represent an immunomodulatory approach to enhance T cell-mediated control of JMML, particularly in the context of HSCT and relapse prevention.

cancer biology↗

bioRxiv2025

Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Background & AimsOncogenic KRAS mutations drive metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to an invariably evolving resistance. MethodsTo understand the metabolic changes induced by dual inhibition, we comprehensively tested cell lines, endogenous tumor models, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes. ResultsWe find that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major mitochondrial alterations, elevates reactive oxygen species (ROS) levels and triggers a lipid peroxidase dependency. While anabolic pathways, glycolysis and autophagy were also affected, mitochondrial alterations persisted longterm into a therapy resistant state. ConclusionsThe resulting vulnerability to induction of ferroptotic cell death via combined SHP2/MEK1/2 and glutathione peroxidase (GPX4) inhibition provides a metabolic lever to reinforce RAS-pathway inhibition for targeted PDAC treatment.

cancer biology↗

bioRxiv2024

The transaminase-omega-amidase pathway is a redox switch in glutamine metabolism that generates alpha-ketoglutarate

Oxidative stress is caused by short-lived molecules and metabolic changes belong to the fastest cellular responses. Here we studied how the endothelial cell metabolome reacts to acute oxidative challenges (menadione or H2O2) to identify redox-sensitive metabolic enzymes. H2O2 selectively increased -ketoglutaramate (KGM), a largely uncharacterized metabolite produced by glutamine transamination and a yet unrecognized intermediate of endothelial glutamine catabolism. The enzyme nitrilase-like 2 {omega}-amidase (NIT2) converts KGM to -ketoglutarate (KG). Reversible oxidation of specific cysteine in NIT2 by H2O2 inhibited its catalytic activity. Furthermore, a variant in the NIT2 gene that decreases its expression is associated with high plasma KGM level in humans. Endothelial-specific knockout mice of NIT2 exhibited increased levels of KGM and impaired angiogenesis. Knockout of NIT2 impaired endothelial cell proliferation and sprouting and induced senescence. In conclusion, we show that the glutamine transaminase-{omega}-amidase pathway is a metabolic switch in which NIT2 is the redox-sensitive enzyme. The pathway is modulated in humans and functionally important for endothelial glutamine metabolism.

physiology↗

bioRxiv2024

Treatment with 2-phospho-L-ascorbic acid mitigates biochemical phenotypes of heme oxygenase 1 deficiency

Heme oxygenase 1 (HO-1) deficiency is a fatal genetic disorder characterized by impaired heme catabolism, leading to excessive oxidative damage and cell death. Despite evidence from non-human models suggesting mitochondrial dysfunction, the precise pathomechanisms in humans remain unclear, resulting in a lack of effective treatments. Using patient-derived lymphoblastoid cells and HO-1 knockout HEK293T cell models, we demonstrate that HO-1 deficiency is associated with altered mitochondrial morphology and impaired mitochondrial function. Furthermore, it is linked to significant ascorbic acid depletion, accompanied by compensatory upregulation of SVCT2, a key ascorbic acid transporter. Treatment with 2-phospho-L-ascorbic acid, a stable vitamin C analog, restores intracellular ascorbic acid levels and protects cells from hemin-induced cytotoxicity, highlighting its potential as a novel therapeutic strategy for HO-1 deficiency. Our study underscores the critical role of oxidative stress and mitochondrial dysfunction in HO-1 deficiency, paving the way for targeted interventions in this devastating disorder.

molecular biology↗

bioRxiv2024

Brain resident macrophages regulate sleep, with repopulated ones being unable to reestablish the original sleep circuits

Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of natural (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states. We found that depletion in embryonically-derived brain macrophages caused increased sleep in the active period, but reduced its quality, reflected in reduced power of brain sleep oscillations. This was observed both for the Non-REM and REM sleep stages. Subsequent repopulation by postnatal brain macrophages unexpectedly failed to reestablish normal sleep-wake patterns and additionally induced sleep fragmentation. Furthermore, brain macrophage depletion caused excitatory-inhibitory synaptic imbalance, which was resistant to repopulation, and led to increased inhibitory synapses. At the metabolite level, the distinct metabolite profile induced by brain macrophage depletion largely returned to normal after repopulation. Our findings suggest a so far largely unknown interaction between brain-resident macrophages and sleep and emphasizes striking functional differences between embryonic and postnatally-derived brain macrophages, paving the way to future exploration of the role of brain macrophages of different origin in sleep disorders and synaptic connectivity.

neuroscience↗