Biology subjects

Yu, Q.

Publications and source records attributed to Yu, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

Habitual sleep duration is associated with the cortical organisation of brain network controllability

Sleep is fundamental to adaptive brain function, yet how habitual sleep relates to the structural network properties that support flexible transitions between brain states remains poorly understood. Combining wrist-accelerometer sleep measures with diffusion MRI connectomes from 15,799 UK Biobank adults, we show that longer workday sleep is associated with higher modal controllability of somatomotor systems and lower controllability of visual cortex. This system-specific signature reproduced in a locked test set (n = 4,740) and was robust across extensive sensitivity analyses. Decomposition showed that it reflects a redistribution of structural connection weight, with greater absolute visual connectivity and a smaller somatomotor share of the whole-brain total. Weekend catch-up sleep showed no comparable association. The signature was distinct from brain-ageing patterns and, across 1,226 phenotypes, related mainly to physical activity and body composition rather than cognition. These findings link everyday sleep habits to the system-specific organisation of brain network controllability.

neuroscience↗

bioRxiv2026

Efferocytosis Remodels Osteoclast Metabolism and Enhances Antibacterial Defense

Osteoclasts are metabolically specialized for bone resorption, but how apoptotic-cell uptake shapes their immune function remains unclear. During Staphylococcus aureus bone infection, osteoclasts engulfed apoptotic neutrophils. In osteoclast cultures, apoptotic-neutrophil exposure reduced multinucleation and resorption, induced host-defense programs, and enhanced antibacterial activity, whereas macrophages showed no comparable antibacterial response. MERTK was required for efficient osteoclast efferocytosis. Ctsk-Cre-mediated Mertk deletion increased bacterial burden and bone loss, whereas transplantation of MERTK-competent bone marrow restored osteoclast efferocytosis and reduced infection-associated bone damage. Transcriptomic and extracellular flux analyses revealed enhanced glycolytic activity and altered lactate handling in efferocytic osteoclasts. Lactate supplementation reduced osteoclast formation without reproducing the antibacterial phenotype. Inhibiting lactate production or export attenuated antibacterial activity in efferocytic osteoclasts, whereas blocking lactate uptake enhanced it. These findings identify osteoclast efferocytosis as an immune adaptation that links apoptotic-neutrophil clearance to metabolic remodeling and antibacterial defense in bone.

cell biology↗

bioRxiv2026

Concurrent anodal tDCS enhances motor learning and increases cortical TrkB phosphorylation

The timing of transcranial direct current stimulation (tDCS) relative to motor practice may influence its behavioral effects, but the accompanying molecular responses remain incompletely characterized. Here, we examined cortical current delivery, rotarod performance, and BDNF-TrkB signaling in mice receiving anodal tDCS concurrently with training or during intertrial intervals. Cortical current measurements indicated that approximately half of the applied current reached the measurement site under the experimental stimulation configuration. During four days of rotarod training, anodal tDCS concurrent with motor tasks improved performance at selected trials and increased footstep frequency, whereas stimulation delivered before or after training trials did not significantly improve performance. Preceding online anodal tDCS with cathodal stimulation provided no detectable additional behavioral benefit. Concurrent anodal tDCS increased TrkB phosphorylation in the stimulated cortex after both one and four days, without a significant increase in BDNF levels. Paused offline anodal tDCS stimulation also increased TrkB phosphorylation after one day despite lacking a detectable behavioral benefit. No significant molecular changes were detected in the sampled non-targeted brain regions. Genetic experiments revealed reduced rotarod performance in BDNF heterozygous mice at several trials and trial-dependent responses to online stimulation in BDNF-KIV mice. Together, these findings show that concurrent anodal tDCS improves rotarod performance and increases TrkB phosphorylation in the stimulated cortex. These results motivate further investigation of how BDNF-TrkB signaling interacts with task-related neural activity during stimulation.

neuroscience↗

bioRxiv2026

Lorentz Tangent Diffusion Adapter for Multi-label Prediction of Protein-Protein Interaction Types

Protein-protein interactions shape cellular organization and disease processes, but their prediction remains difficult because known interaction networks are incomplete, noisy and highly uneven across proteins. Hyperbolic graph learning is well suited to the hierarchical structure of such networks, yet most methods emphasize learning hyperbolic embeddings and pay less attention to how these embeddings are propagated and decoded for type prediction. Here we introduce the Lorentz Tangent Diffusion Adapter (LTDA), a post-embedding module for PPI type prediction, that is, for predicting which of several interaction types a candidate protein pair undergoes. LTDA learns relation-specific protein representations on the Lorentz manifold, projects them to tangent space, applies lightweight graph diffusion, and decodes the diffused representations directly in tangent space. This design uses the tangent space as a prediction-oriented interface between hierarchical representation learning and interaction classification. On SHS27K and SHS148K under BFS and DFS splits, LTDA consistently improves over representative PPI methods and a reproduced HI-PPI baseline, with average gains of 1.41 percentage points in Micro-F1, 3.21 in AUPR, 1.31 in AUC and 1.25 in accuracy. Ablation, degree-bin and biological-evidence analyses indicate that the gains are not explained by simple smoothing or hub correction. LTDA therefore shows that post-embedding adaptation can make Lorentz representations more effective for PPI type prediction.

bioinformatics↗

bioRxiv2026

KRASG12C Inhibition Remodels the Non-Small Cell Lung Cancer Surfaceome to Uncover Targetable Vulnerabilities

Mutant-selective and pan-RAS(ON) multi-selective inhibitors have improved clinical outcomes for patients with RAS-driven cancers; however, adaptive resistance limits the depth and durability of response. Using an integrated genetic, transcriptomic, and mass-spectrometry-based quantitative temporal proteomic platform, we profile the adaptive response to KRASG12C inhibitors (KRASi) in KRASG12C-mutant lung adenocarcinoma models. Our analyses reveal remodeling of signaling pathways and the cell surface proteome, including cell surface proteins selectively upregulated across cell lines, tumor models, and treatment durations. Folate receptor alpha (FOLR1) emerged as a therapeutically actionable target that is significantly upregulated with KRASi and is part of a broader acute cellular state transition characterized by acquisition of an epithelial identity. Combining KRASi with mirvetuximab soravtansine-gynx, a clinically approved FOLR1-targeting antibody drug conjugate, enhanced tumor cell cytotoxicity and deepened response and tumor control in cellular and in vivo models. Additionally, this work represents a comprehensive multi-omic resource characterizing non-genetic temporal adaptation to KRASi for future mechanistic and therapeutic investigations.

cancer biology↗

bioRxiv2026

KRAS inhibition drives adaptive surfaceome remodeling and reveals ALPP/ALPPL2 as a targetable vulnerability in pancreatic cancer

KRAS is mutated in over 90% of pancreatic ductal adenocarcinoma (PDAC) and is required for tumor initiation and maintenance. While clinical trials testing mutant-selective and pan-RAS inhibitors (KRASi) have demonstrated significant clinical benefit, genetic and non-genetic mechanisms of resistance limit the long-term efficacy of monotherapy strategies. Here, we used quantitative temporal analysis of the global, phosphorylation, and surface proteome to comprehensively identify non-genetic adaptive pathways and cell surface biomarkers in response to acute and long-term KRAS inhibition in PDAC. Through integrative machine learning analysis of the KRASi-proteome and publicly available datasets, we discovered top priority cell surface targets for combination therapy with KRASi. We identified Placental Alkaline Phosphatase (ALPP) as upregulated in response to KRASi through compensatory JAK2/STAT3 signaling. We developed a novel clinical grade ALPP/ALPPL2 (ALPG)-targeting antibody drug conjugate (ADC) with site-specific MMAE conjugation and demonstrated single agent efficacy in PDAC models, as well as enhanced internalization and anti-tumor efficacy in combination with KRASi. Together, these studies comprehensively define the KRASi-induced proteome and identify ALPP/ALPPL2 as a promising cell surface target for combination with KRASi to enhance response and forestall KRASi resistance.

cancer biology↗

bioRxiv2026

Seizures in a Dravet Syndrome mouse model inhibit the locus coeruleus but locally evoke supraphysiologic norepinephrine release

Locus coeruleus (LC) neurons are the primary source of norepinephrine / noradrenaline (NE) released to most brain structures, including seizure-prone neocortical and limbic regions. LC-NE networks regulate numerous physiological processes, including arousal, attention, and memory. Previous evidence suggests that LC-NE neurons may be involved in epilepsy and that their activation may have therapeutic effects on seizures, but the endogenous activity of the LC-NE network during seizures remains largely unclear. We combined electrocorticography recordings and in vivo imaging to measure somatic activity of LC-NE neurons as well as downstream NE release during hyperthermia-induced seizures in a well-characterized pre-clinical model of Dravet Syndrome. We found that population LC-NE somatic activity was inhibited during seizures, whereas downstream NE release was dramatically elevated. To reconcile these discordant findings, we established that activation of downstream regions is capable of locally evoking NE release, in part via activation of glutamate receptors, consistent with the Glutamate Amplifies Noradrenergic Effects (GANE) model. Finally, we confirmed that ictal NE release occurred across additional downstream brain regions, epilepsy models, and seizure induction methods. Thus, disruption of NE signaling is likely a widespread ictal signature, with implications for impaired consciousness during and after seizures.

neuroscience↗

bioRxiv2026

A multivalent docking platform and Rcn1-mediated inhibition control the extent of calcineurin recruitment to the cell division site for the dephosphorylation of multiple cytokinetic proteins

Cytokinesis requires coordinated signaling to ensure the accurate physical separation of daughter cells. Calcineurin (CN), a conserved Ca2+/calmodulin-dependent phosphatase, is required for cytokinesis in organisms ranging from yeast to humans, yet how CN is regulated at the division site and the substrates through which it promotes cell division remain poorly understood. Here we use the fission yeast Schizosaccharomyces pombe, which display striking cell division defects in the absence of CN, to define how CN is anchored at the cell division site. We show that CN recruitment to the cytokinetic ring (CR) requires its PxIxIT- and LxVP-binding surfaces and is mediated by multivalent interactions with the CR components paxillin-like Pxl1 and the F-BAR protein Cdc15. Disrupting these interactions nearly eliminates CN from the CR and causes gross cytokinetic defects similar to complete loss of CN function. Cell cycle stage-specific quantitative phosphoproteomics combined with proximity labeling-based proteomics were used to identify candidate CN substrates involved in cytokinesis. Validation of a cohort of these proteins localizing to the CR, including the F-BAR protein Rga7, the actin regulator Aim21 and three protein kinases, revealed that CN targets a broad network of structural and signaling components involved in cell division. We also identify the conserved CN inhibitor Rcn1 as a CN substrate and show that Rcn1 restricts CN accumulation at the CR to provide an additional layer of spatial regulation. Thus, spatial control of CN enables proper protein dephosphorylation for successful cytokinesis.

cell biology↗

bioRxiv2026

Helicase-deficient TFIIH causes severe disease features via persistent DNA excision without damage removal

Nucleotide excision repair (NER) removes helix-distorting DNA lesions through the ten subunit TFIIH complex, whose XPB and XPD translocase/helicase activities unwind DNA to enable damage verification and subsequent endonucleolytic DNA incisions. While most XPD mutations cause xeroderma pigmentosum, specific helicase-deficient mutations cause severe Cockayne syndrome (CS) features, including progressive neurodegeneration, for which the basis remains unclear. Here we show that loss of XPD helicase activity traps TFIIH in a futile repair cycle in which DNA is incised at the wrong position, leading to repeated DNA excision and resynthesis without removal of the lesion. Using C. elegans, we find that this futile DNA excision cycle produces severe neuronal dysfunction in vivo that depends on transcription-coupled NER activity and is rescued by preventing recruitment of helicase deficient TFIIH. These findings demonstrate that NER incisions can occur without XPD mediated damage verification and that persistent futile DNA excision cycles cause severe disease features, indicating that persistent NER intermediates are more pathogenic than unrepaired DNA lesions.

genetics↗

bioRxiv2026

TomatoPGFM: A graph-conditioned foundation model for tomato pangenomes

Most genomic foundation models are pretrained on independent linear assemblies and therefore do not explicitly represent population-level segment sharing or local graph connectivity. We developed TomatoPGFM, a graph-conditioned model pretrained on 54.65 Gb of sequence from 66 tomato (Solanum spp.) accessions. Sequence tokens were conditioned on pangenome node attributes and local adjacency, and the model was optimised using masked language modelling and graph-feature reconstruction. To evaluate model responses to graph-conditioned input, we compared aligned, shuffled and disabled graph inputs in 25,000 windows from the training panel. Sequence-aligned graph input produced lower masked language modelling loss than graph-off at all five curriculum stages in both training-panel strata, while the shuffled perturbation generally yielded intermediate losses. We then assessed sequence-only transfer in Solanum sitiens LA1974 and S. lycopersicum MicroTom, neither of which was used for graph construction or pretraining. Frozen-probe AUROC values for gene-versus-intergenic and coding-sequence-versus-intergenic classification ranged from 0.8489 to 0.9593. TomatoPGFM produced higher AUROC point estimates than DNABERT-2 in all four comparisons. Enabling the zero-feature GraphAdapter pathway with adjacency messaging disabled changed throughput by less than 1% at 512-2,048 positions under the tested configuration. Together, these results show that TomatoPGFM responds consistently to sequence-aligned pangenome context in training-panel sequences and provides informative sequence representations for genic-region classification in accessions excluded from graph construction and pretraining.

bioinformatics↗

bioRxiv2026

In Vivo Screening for a Promising Antiparasitic Agent Against Neobenedenia melleni in Epinephelus fuscoguttatusfemale x E. lanceolatusmale and Identification of Its Potential Target

Monogenean ectoparasites, particularly Neobenedenia species, cause severe economic losses in mariculture. Here, ectoparasites isolated from cultured hybrid groupers (Epinephelus fuscoguttatus[female] x E. lanceolatus[male]) were confirmed as Neobenedenia melleni based on ITS1 phylogeny. In vivo screening of six structurally diverse compounds identified compound D (CAS No. 206111-37-7), a 5,6-dihydropyridine derivative, as the most effective antiparasitic agent, achieving 76.54% efficacy at 0.5 mg/L in a 90 min bath treatment. Dose-response assays demonstrated that 0.7 mg/L compound D achieved 95.23% antiparasitic efficacy without causing evident tissue damage or cytotoxicity to GF-1 cells. Ultrastructural observation by scanning electron microscopy revealed marked tegumental alterations, including deep fissures and extensive surface folding, in treated parasites. Molecular docking against ten candidate proteins identified {beta}-tubulin as the most favorable docking target, with a binding energy of -6.53 kcal/mol and three hydrogen-bond interactions, suggesting that {beta}-tubulin may be involved in the antiparasitic activity of compound D. Overall, these findings highlight compound D as a promising lead candidate for short-bath therapy against N. melleni and suggest that cytoskeletal disruption through {beta}-tubulin interaction represents a plausible mechanism of action.

zoology↗

bioRxiv2026

A multimodal representation learning platform for accurate molecular ADMET prediction

Accurate ADMET prediction is essential for prioritizing compounds before costly experimental validation, yet ADMET tasks are highly heterogeneous. Properties such as solubility, permeability, protein binding, clearance, transporter activity and toxicity are governed by different molecular signals, ranging from local functional groups and physicochemical descriptors to bonded topology and three-dimensional geometry. Consequently, a single molecular representation or backbone is unlikely to be optimal across all ADMET tasks. We present Trimole-Hybrid, a task-wise multimodal framework that addresses ADMET heterogeneity by selecting or combining predictors built from complementary molecular representations. Trimole-Hybrid constructs a candidate pool of SMILES-, graph-, geometry-sensitive EPT/3D- and chemical descriptor-based predictors. For each task, Trimole-Hybrid selects the best-performing predictor to obtain the final prediction. On 22 Therapeutics Data Commons ADMET benchmarks, Trimole-Hybrid exceeded the public TDC top-1 methods on 10 tasks and ranked within the top 10 for 21 tasks. Ablation studies confirmed the contribution of both complementary multimodal molecular representations and task-specific ensemble strategies. In two small-molecule case studies, Trimole-Hybrid shows sensitivity to changes in essential functional motifs, suggesting its ability to capture ADMET-relevant molecular substructures.

bioinformatics↗

bioRxiv2026

Computer-aided drug screening of anti-Neobenedenia melleni drugs based on annexin B1 in farmed pearl grouper

Monogenean capsalids of the genus Neobenedenia are widespread parasites of wild and farmed marine fish, and represent a great threat to the mariculture of grouper in China. Fishery drug development to screen and find effective compounds to control and prevent the disease is urgent needed, considering the vast production of grouper in China (294 ktons in 2025). Annexins have been discovered in Neobenedenia and other parasites, and marked differences between the parasite annexins and those of the hosts make them potentially attractive drug targets for anti-parasite therapeutics. Herein, we utilized computer-based drug discovery screens using unique Neobenedenia melleni annexin B1 and a database of 1,456,161 small molecules. The 3D structure of annexin B1 was firstly modeled by three different protein prediction tools, namely AlphaFold 3, SWISS-MODEL, and I-TASSER, of which the most accurate protein structure was used as the drug target for the following structure-based virtual screening. In vivo experimental validation of 11 compounds after molecular docking shows that abamectin (Aba) has the most effective anti-Neobenedenia bioactivity at the concentration of 0.16 mg/L as the initial screening concentration. Given its low toxicity to host grouper (24 LC50=0.254 mg/L), abamectin was chose for further investigation. A 24 h bath exposure successfully lowered the parasitic load in infected grouper, yielding an 24 h EC50 of 0.033 mg. To elucidate the anti-parasite mechanism, long-timescale molecular dynamics simulations (1000 ns) of annexin B1 and Aba was conducted, which allowed for atomic and molecular-level analysis of the essential protein motions involved in the interaction of annexin B1 and its substrate. The interaction profile between annexin B1 and abamectin was dominated by hydrophobic contacts and water bridges, involving residues TYR-210, GLU-214, GLU-244, and SER-247, which path a way for further drug optimization.

zoology↗

bioRxiv2026

WHaloForce enables chemigenetic imaging of molecular tension in living cells and animals

Piconewton forces borne by individual proteins within complex assemblies underlie cell adhesion, migration, and tissue morphogenesis, yet remain difficult to image in living systems. Here, we introduce WHaloForce, a chemigenetic HaloTag-based tension sensor that converts force-dependent relief of tryptophan-mediated dye quenching into a fluorescence lifetime change. Optical tweezers revealed a switch-like unquenching transition near 5 pN, and the sensor responded reversibly to force changes in cells. WHaloForce enabled quantitative tension imaging of diverse force-bearing proteins (vinculin, E-cadherin, -catenin, and laminin) in mammalian cells, mouse tissue, and C. elegans. Bright synthetic dyes made tension measurements possible at endogenous expression levels. In C. elegans, vinculin and laminin showed opposite tension patterns between tissues, revealing distinct force-transmission routes through adhesions and the extracellular matrix. During ovulation, laminin tension accumulated over repeated stretch-relaxation cycles, scaling with cumulative loading history. WHaloForce thus offers a modular platform for imaging spatiotemporal tension patterns in living systems.

cell biology↗

bioRxiv2026

In vivo reconstruction of the cell lineage history of a developing mouse with DNA Typewriter, from zygote to late organogenesis

The complete cell lineage of C. elegans, mapped over four decades ago, was tractable because the animal is small, transparent, and lineage invariant1. Most animals are none of these, having orders of magnitude more cells, being opaque, and developing with substantial stochasticity2. Since 2016, genome editing-based lineage tracing has opened the door to dense cell lineage reconstruction in such organisms3-8, but delivering on that promise has proven technically challenging. Here we apply DNA Typewriter9-11, a prime editing-based recorder that writes stochastic symbolic insertions to an engineered genomic TAPE in strictly sequential order, to trace mouse development from zygote (E0) to late organogenesis (E13.5). We introduce constructs encoding a prime editor, engineered prime editing guide RNAs (epegRNAs), and Pol-III-driven circularized TAPE RNA (circTAPE) into wildtype zygotes by pronuclear injection (PNI), then assay embryos by single-nucleus transcriptional profiling (sci-RNA-seq3)12 with paired circTAPE recovery. From one E13.5 embryo bearing [~]7 integrations of a constitutively expressed prime editor and 11 integrations of 6-unit circTAPE, we recover [~]1.75M single-nucleus transcriptomes and reconstruct a time-calibrated phylogeny of 1,340,794 annotated cells with parsimony-based node support. The first cell division is marked unequivocally, and although the resulting blastomeres contribute asymmetrically to the embryo proper, they are fate-neutral and serve as internal replicates that reproduce every finding. A modest cohort of pre-gastrulation founders dominates the embryo, with inequality exceeding neutral expectation within one to two cell cycles of founder allocation, yet these founders remain broadly multipotent; a second phase of clonal dominance arises in specific lineages during organogenesis. At the finest scale, sibling cells share cell type 9-fold in excess of chance, reaching 68- to 107-fold for cell types arising from spatially restricted founder pools, while the recent differentiations of organogenesis are legible in the heterotypic structure of terminal clades. From clade co-occurrence alone, we recover germ-layer organization and a dated hierarchy of cell-type couplings with branch points from E8.5 onwards. Finally, by integrating these data with our single-cell time-series of mouse development13, we impute transcriptional states and annotations for the majority of internal nodes and recover established state histories for diverse cell types. All data are made freely available, together with NextCell, an interactive browser for this annotated cellular phylogeny of mouse development from zygote to late organogenesis.

developmental biology↗

bioRxiv2026

A minimal kinase-phosphatase system and its lipid substrates self-organize into dynamic patterns

Competing lipid kinases and phosphatases are critical for organizing cellular membranes, but whether a minimal system can autonomously organize proteins and lipids into dynamic spatiotemporal patterns is unknown. Here, we report the in vitro reconstitution of the Legionella phosphatidylinositol (PI) 3-kinase MavQ and PI 3-phosphatase SidP. Together with their lipid substrates, PI and PI 3-phosphate (PI3P), these enzymes form a minimal self-organizing system that generates ATP-dependent spatiotemporal patterns, including traveling waves, on model membranes. These behaviors arise from MavQs cooperative membrane binding, SidPs phosphatase activity, and the continual interconversion and redistribution of PI and PI3P within a conserved membrane pool. A reaction-diffusion model reproduces the observed dynamics and predicts that lipid conservation prevents patterns from propagating across membrane discontinuities, which we verify experimentally. Together, these findings establish enzymatic modification of membrane lipids as a distinct molecular strategy for biological pattern formation.

biophysics↗

bioRxiv2026

Integrative computational toxicology reveals PFOS and PFHxS associated inflammatory keratinocyte niches in psoriasis through exposure transcriptomics, single-cell spatial mapping and token-aware virtual perturbation

Per- and polyfluoroalkyl substances (PFAS) are persistent toxicants with immunological, metabolic and epithelial effects, but their relevance to inflammatory skin disease remains unclear. We developed a computational toxicology framework to test whether perfluoroalkyl sulfonate programs, especially perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS), converge with psoriasis-associated keratinocyte inflammation. Exposure transcriptomes were derived from GSE236956, in which human embryonic stem cell-derived epithelial-lineage models were exposed to 10 M PFAS for 8-16 days. Six PFAS were prioritized using descriptors, Tanimoto similarity, toxicology evidence, adverse outcome pathway (AOP)-like key events, exposure differentially expressed gene burden and read-across support. PFAS signatures were integrated with psoriasis bulk transcriptomes, single-cell RNA sequencing, keratinocyte-state mapping, regulator and communication inference, spatial transcriptomics and token-aware Geneformer-compatible virtual perturbation. PFOS ranked highest in integrated prioritization, followed by PFHxS and perfluorooctanoic acid. PFHxS produced a smaller but directionally informative signature within a PFOS-dominant perfluoroalkyl sulfonate footprint. The shared PFOS and PFHxS program converged with psoriasis through inflammatory keratinocyte, epidermal-stress, cytoskeletal and lipid-related modules. Single-cell and spatial analyses localized the program to activated keratinocytes and inflammatory epidermal niches, with strong spatial co-localization with inflammatory keratinocyte and epidermal stress scores. Virtual perturbation prioritized S100A9, S100A8, KRT16, IL36G, CCL20, CXCL8, FABP5, KRT17, FOS, JUN and NFKBIZ as candidate effectors. These findings support an exposure-informed, experimentally testable hypothesis linking persistent perfluoroalkyl sulfonate programs to keratinocyte inflammatory niches in psoriasis.

bioinformatics↗

bioRxiv2026

Spatiotemporal biosensor profiling reveals an autonomous mitochondrial NAD+/NMN regulatory network centered on NMNAT3

Nicotinamide adenine dinucleotide (NAD+) and its precursor nicotinamide mononucleotide (NMN) are strictly compartmentalized, yet how individual organelles maintain local metabolic homeostasis remains unresolved. Here, we report FrNADS and FrNMNS1.0, a FRET-based biosensor toolkit that maps NAD+ and NMN dynamics in living cells with subcellular resolution, including the oxidizing lumen of the endoplasmic reticulum. We find that NAD+ recovery in the nucleus following PARP1 activation depends on NAMPT mediated salvage synthesis, while peroxisomes buffer NAD+ via NUDT12 and SLC25A17. In mitochondria, NMNAT3 acts as a NAD+ hydrolase that counterbalances import through SLC25A51; HINT2 functionally enhances this activity. Furthermore, SLC25A48 functions as a critical regulatory node that modulates the compartmental redistribution of the generated NMN. These findings establish a mitochondrial NAD+/NMN regulatory circuit and reveal how organelles independently resolve metabolic stress.

cell biology↗