Biology subjects

Soga, T.

Publications and source records attributed to Soga, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Renal nutrient loss promotes metabolic health at the expense of increased vulnerability to acute kidney injury

Obesity is a major risk factor for interrelated cardiorenal metabolic diseases including type 2 diabetes, heart failure and chronic kidney disease (1-4). Although obesity develops when energy intake chronically exceeds energy expenditure, individuals vary markedly in the amount of adiposity and metabolic dysfunction that develop in response to comparable caloric excess. Controlled overfeeding studies demonstrate several-fold variation in weight gain between individuals (5), while susceptibility to metabolic dysfunction also differs substantially between populations (6), suggesting considerable variation in how excess nutrients are partitioned. Energy balance is conventionally considered in terms of intake and expenditure, yet energy-containing nutrients can also be eliminated from the body. The kidney is uniquely positioned to regulate this third component of energy balance by determining whether filtered metabolites are reabsorbed or excreted. The metabolic benefits of SGLT2 inhibition demonstrate that reducing renal nutrient reabsorption can favourably alter systemic metabolic function (7,8), but whether naturally occurring variation in renal nutrient conservation contributes to metabolic disease susceptibility remains unknown. Here, screening eleven genetically divergent mouse strains identified BXD34 mice as strikingly resistant to diet-induced obesity, ectopic lipid accumulation and insulin resistance despite increased caloric intake. Mechanistically, this protection was associated with widespread urinary nutrient loss accompanied by coordinated suppression of renal solute transport, but came at the cost of profound susceptibility to acute kidney injury. Together, these findings identify renal nutrient conservation as an underappreciated determinant of whole-body metabolism and reveal a renometabolic trade-off in which protection from obesity is achieved at the expense of renal resilience.

physiology↗

bioRxiv2026

Mitochondrial one-carbon enzyme MTHFD1L sustains stemness and metastatic progression in breast cancer

One-carbon (1C) metabolism is frequently upregulated in cancer to support anabolic growth and nucleotide biosynthesis. However, the contribution of mitochondrial 1C metabolism to cancer stemness and metastatic progression remains incompletely understood. Here, we identify methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L), a mitochondrial 1C metabolic enzyme, as a critical regulator of breast cancer stemness, tumor initiation, and lung metastasis. Genetic depletion of MTHFD1L in triple-negative breast cancer (TNBC) cell lines and patient-derived breast cancer models markedly impaired proliferation, sphere formation, tumorigenicity, and lung colonization. Metabolomic profiling revealed extensive metabolic rewiring following MTHFD1L loss, characterized by accumulation of the purine biosynthetic intermediates SAICAR and AICAR together with perturbations in glycolytic and pentose phosphate pathways. Importantly, suppression of lung metastasis was accompanied by reduced expression of the stemness-associated transcription factor SOX2 and decreased proliferative activity in metastatic lesions. Collectively, our findings establish MTHFD1L as a key metabolic dependency linking mitochondrial 1C metabolism to stem-like properties and metastatic progression in breast cancer, and highlight MTHFD1L as a promising therapeutic target in metastatic TNBC.

Cancer Biology↗

bioRxiv2026

Epithelial Glutamate Retention Protects against Colitis

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses ulcerative colitis and Crohns disease. Here we identify the cystine/glutamate antiporter xCT as being markedly upregulated in the inflamed intestinal epithelium of patients with IBD. To clarify its functional contribution to disease pathogenesis, we performed genetic loss-of-function study and found that inhibition of xCT confers robust protection against dextran sulfate sodium (DSS)-induced colitis in mice. Intestinal epithelial cell (IEC)-specific deletion of xCT markedly attenuated colitis severity, demonstrating that epithelial xCT upregulation acts as a disease-exacerbating factor in IBD. Mechanistically, xCT deficiency preserved intracellular glutamate levels and protein polyglutamylation, thereby maintaining epithelial barrier integrity and protecting IECs from inflammatory injury. Consistently, pharmacological inhibition of glutamine synthetase, which increases intracellular glutamate, exerted a potent anti-inflammatory effect on the DSS-induced colitis. These findings identify intracellular glutamate retention in IECs as a previously unrecognized mechanism of epithelial protection and highlight both inhibition of xCT-dependent glutamate efflux and suppression of glutamine synthetase as potential therapeutic strategies for IBD.

molecular biology↗

bioRxiv2026

Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host-microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naive patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.

cancer biology↗

bioRxiv2026

A chorionic gonadotropin assay enables non-invasive detection of ovulation and early pregnancy in a New World primate model

Early detection of ovulation and pregnancy in the common marmoset is crucial for reproductive studies, yet hCG kits lack cross-reactivity with marmoset CG, and current methods remain labor-intensive. Here, we developed monoclonal antibodies against marmoset CG and CG{beta}, and established a non-invasive immunochromatographic CG assay. By eliminating invasive blood sampling, this assay supports 3Rs principles and enables practical endocrine monitoring. The assay detected urinary CG surges preceding ovulation, enabling efficient embryo recovery through artificial insemination (75%). Early pregnancy was detected at approximately 17 days post-ovulation. In addition, pregnancy detection in squirrel monkeys suggests conservation of CG features among certain New World primates. Overall, this simple, non-invasive assay provides a practical tool for marmoset research and establishes a foundation for future conservation-oriented reproductive monitoring following appropriate species-specific validation.

physiology↗

bioRxiv2025

The Gibbs free energy landscape based on liver metabolome revealed thermodynamic robustness against fasting and obesity

Mammalian liver metabolism undergoes a substantial shift during fasting. Thermodynamic principles impose fundamental constraints on metabolism, and the Gibbs free energy change of reaction ({Delta}rG') indicates the reactions direction and distance from equilibrium. However, {Delta}rG' landscapes in intact mammalian organs remain largely uncharacterized. Here, we mapped {Delta}rG' profile of glucose metabolism in mouse liver during fasting, using experimentally measured absolute metabolite concentrations and a newly developed computational method, GLEAM. We found that despite large metabolite fluctuations during fasting, the corresponding {Delta}rG's remained robust, even for reactions reversing the direction between glycolysis and gluconeogenesis. A remarkable thermodynamic robustness is found in maintaining potential candidates of rate-limiting steps during fasting. This robustness is achieved by expending substantial costs for enzyme expressions, contributing to efficient switching from glycolysis to gluconeogenesis. Furthermore, obese mouse liver also showed thermodynamic robustness despite obesity-induced metabolic disruption. Our framework provided a novel thermodynamic perspective on intact organ metabolism, demonstrating that the liver robustly maintains thermodynamic characteristics favorable for metabolic control by buffering metabolite concentration differences.

systems biology↗

bioRxiv2025

Global loss of responsiveness in key regulator metabolites and elevated enzyme proteins as metabolic dysregulation in skeletal muscle and liver of obese mice during starvation

Starvation induces complex metabolic adaptations in skeletal muscle, a key tissue for maintaining energy homeostasis; however, these adaptations are largely impaired in obesity. How obesity alters global metabolic adaptations to starvation in skeletal muscle remains unclear. Here, we analyzed the metabolic adaptations on a trans-omics scale during starvation in skeletal muscle from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We measured multi-omics data during starvation and constructed global trans-omics networks in WT and ob/ob mice. We found that starvation induces "responsiveness" in WT mice, characterized by increases or decreases in key regulator metabolites, including ATP and AMP, as well as enzyme proteins, leading to global regulation of metabolic pathways, which was lost in ob/ob mice. In contrast, during starvation, ob/ob mice exhibit "difference" in comparison to WT mice, manifested by the persistently elevated expression of metabolic enzymes. These features were similarly found in liver, another key metabolic organ. Thus, global loss of responsiveness and elevated enzyme proteins are systemic features of metabolic dysregulation in ob/ob mice.

systems biology↗

bioRxiv2024

Identifying simultaneous inhibition of riboflavin metabolism and MEK as a novel therapeutic strategy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge with a survival rate of approximately 10%, largely due to the lack of diagnostic and therapeutic options. To identify novel therapeutic targets for PDAC, we previously developed a Drosophila melanogaster model, the 4-hit fly, which mimics the alterations in KRAS, TP53, CDKN2A, and SMAD4 genes observed in PDAC. Through whole-body genetic screening using the 4-hit model, we identified riboflavin (RF) metabolism as a novel potential therapeutic target for PDAC. Additionally, transcript levels of four out of five genes that are involved in RF metabolism were elevated in human PDAC compared to non-tumor tissues. Roseoflavin (RoF), an antimetabolite of RF, resulted in a variety range of metabolic changes, decreased mitochondrial respiratory chain activity, and suppressed proliferation in cultured PDAC cells. Furthermore, the combination of RoF with the MEK inhibitor drug trametinib significantly suppressed the growth of human PDAC xenografts compared to either treatment alone. These findings underscore that dual targeting of RF metabolism and MEK represents a novel therapeutic strategy for PDAC.

cancer biology↗

bioRxiv2024

In silico screening by AlphaFold2 program revealed the potential binding partners of nuage-localizing proteins and piRNA-related proteins

Protein-protein interactions are the fundamental features for understanding the molecular functions and regulations of proteins. Despite extensive databases, many interactions remain uncharacterized due to the intensive labor required for experimental validation. In this study, we utilized the AlphaFold2 program to predict interactions among proteins localized in the nuage, a germline-specific non-membrane organelle critical for piRNA biogenesis and RNA regulation. We screened 20 types of nuage proteins for 1:1 interactions and predicted dimer structures. Among those, five pairs represented novel interaction candidates. Three pairs, including Spn-E_Squ, were validated through co-immunoprecipitation in cultured cells and confirmed the interactions. Disruption of the salt bridges at the Spn-E_Squ interface verified their functional importance, underscoring the predictive models accuracy. Our analysis was extended to include interactions between three representative nuage components, Vas, Squ, and Tej, and approximately 430 oogenesis-related proteins. Following this extended analysis, co-immunoprecipitation in S2 cells verified interactions for three pairs: Mei-W68_Squ, CSN3_Squ, and Pka-C1_Tej. Furthermore, the majority of Drosophila proteins, [~]12,000, were screened for the interaction with Piwi protein, a central player in the piRNA pathway. Approximately 1.5% of the pairs, totaling 164 pairs, with a score above 0.6, were identified as potential binding partners. This in silico approach not only efficiently identifies potential interaction partners but also significantly reduces the gap by facilitating the integration of bioinformatics and experimental biology.

molecular biology↗

bioRxiv2024

Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in liver of healthy and obese mice

Adaptation to starvation is a multi-molecular and temporally ordered process, that could be impaired in obesity. To elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process, we measured time course multiomic data in the liver of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation. Using the measured data, we constructed a starvation-responsive metabolic network, that is a transomic network including responsive molecules and their regulatory relationships during starvation, and analyzed the structure of the network. In WT mice, ATP and AMP, the energy indicators, regulated various metabolic reactions in the network as the hub molecules, both of which were not responsive in ob/ob mice. However, the structural properties of the network were maintained in ob/ob mice. In WT mice, the molecules in the network were temporally ordered through metabolic process coordinated by the hub molecules including ATP and AMP and were positively or negatively co-regulated. By contrast, both temporal order and co-regulation were disrupted in ob/ob mice. Taken together, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity. In addition, we proposed a potential therapeutic target to treat the negative effects of obesity on intermittent fasting to extend lifespan. One Sentence SummaryHub molecules activate or inhibit various molecules in a temporally ordered manner in healthy liver, and the regulatory network is structurally robust but temporally vulnerable to obesity.

systems biology↗

bioRxiv2023

Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding, and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h-fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations, activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

systems biology↗

bioRxiv2023

Gut microbiome-based prediction of autoimmune neuroinflammation

Gut commensals are linked to neurodegenerative diseases, yet little is known about causal and functional roles of microbial risk factors in the gut-brain axis. Here, we employed a pre-clinical model of multiple sclerosis in mice harboring distinct complex microbiotas and six defined strain combinations of a functionally-characterized synthetic human microbiota. Discrete microbiota compositions resulted in different probabilities for development of severe autoimmune neuroinflammation. Nevertheless, assessing presence or the relative abundances of a suspected microbial risk factor failed to predict disease courses across different microbiota compositions. Importantly, we found considerable inter-individual disease course variations between mice harboring the same microbiota. Evaluation of multiple microbiome-associated functional characteristics and host immune responses demonstrated that the immunoglobulin A-coating index of Bacteroides ovatus before disease onset is a robust individual predictor for disease development. Our study highlights that the "microbial risk factor" concept needs to be seen in the context of a given microbial community network, and host-specific responses to that community must be considered when aiming for predicting disease risk based on microbiota characteristics.

microbiology↗

bioRxiv2022

Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via PDH regulation

A high-salt diet significantly impacts various diseases, including cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, the PDH phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmo-sensing mechanism. Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of PDH phosphorylation by direct osmosensing within mitochondria.

cell biology↗

bioRxiv2022

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and genetically obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

systems biology↗

bioRxiv2021

Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors

Ribosome biogenesis involves the processing of precursor ribosomal RNAs (pre-rRNAs) and sequential assembly with ribosomal proteins. Here we report that nutrient deprivation severely impairs pre-rRNA processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, the accumulated pre-rRNAs are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient deprivation leads to perturbed ribosome assembly during nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine was dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which was in turn dependent on Raf/MEK/ERK signalling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that cancer cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

cancer biology↗

bioRxiv2021

HSD11β1 promotes EMT-mediated breast cancer metastasis

Abnormal biosyntheses of steroid hormones and dysregulation of steroid hormone receptors contribute to breast cancer metastasis but the mechanisms of that are poorly understand. Here we report a stress hormone producing enzyme, Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11{beta}1) promotes breast cancer metastasis. HSD11{beta}1 was ectopically expressed in seventy-one percent of triple-negative breast tumors and correlated with shorter overall survival. HSD11{beta}1 significantly promoted breast cancer metastasis through induction of epithelial-to-mesenchymal transition (EMT); conversely, pharmacologic and genetic inhibition of HSD11{beta}1 suppressed metastatic progression of breast cancer cells. Moreover, 11-hydroxyprogesterone (11-OHP) whom HSD11{beta}1 produced in breast cancer cells, conferred metastatic properties on non-metastatic breast cancer cells through induction of EMT. We identified Peroxisome Proliferator-activated Receptor Alpha (PPAR-) as essential for both HSD11{beta}1 and 11OHP-driven EMT. Knockdown of PPAR- induced MET on HSD11{beta}1-expressing breast cancer cells. Taken together, HSD11{beta}1 promotes breast cancer metastasis and would be a novel target for suppressing breast cancer metastasis.

cancer biology↗

bioRxiv2021

Omics-based label-free metabolic flux inference reveals dysregulation of glucose metabolism in liver associated with obesity

Glucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify changes in metabolic flux, and to quantify contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in liver. HighlightsO_LIWe created OMELET to infer metabolic flux and its regulation from multi-omic data. C_LIO_LIGluconeogenic and pyruvate cycle fluxes increased in fasting ob/ob mice. C_LIO_LITranscripts increases mediated the increase in gluconeogenic fluxes in ob/ob mice. C_LIO_LIIncreases in transcripts and substrates enhanced pyruvate cycle flux in ob/ob mice. C_LI

systems biology↗

bioRxiv2020

Thiazoline-related TRPA1 agonist odorants orchestrate survival fate in mice

Therapeutic hypothermia protects the brain after cardiopulmonary arrest. Innate fear has evolved to orchestrate protective effects in life-threatening situations. Thus, strong fear perception may induce a specialized life-protective metabolism based on hypothermia/hypometabolism; however, such phenomena and their inducers are yet to be elucidated. Here, we report that thiazoline-related fear odors (tFOs), which are TRPA1 agonists and induce robust innate fear in mice, induced hibernation-like systemic hypothermia/hypometabolism, accelerated glucose uptake in the brain, and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment. In contrast to hibernation, during which immune functions are generally suppressed, tFO-stimulation induced a crisis-response immune state characterized by potentiated innate immune functions but suppressed inflammation with anti-hypoxic ability. Collectively, these responses exerted potent therapeutic effects in cutaneous and cerebral ischemia/reperfusion injury models. Whole brain mapping and chemogenetic activation revealed that sensory representation of tFOs orchestrate survival fate via brain stem Sp5/NST to midbrain PBN pathway. TFO-induced strong crisis perception maximizes latent life-protective effects by shifting metabolism to a crisis response mode characterized by hypothermia, hypometabolism and crisis immunity.

physiology↗