Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Rare insights into cancer biology

Adam, J., Yang, M., Soga, T., and Pollard, P.J.

Oncogene 33 ( 20 ) 2547 - 2556 2014.05

Research paper (scientific journal), Joint Work, Accepted

Cancer-associated mutations have been identified in the metabolic genes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent dioxygenases, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases, JmjC domain-containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways and inhibition of histone and DNA demethylation. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology associated with dysregulated metabolism and represents a useful paradigm for cancer research.

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Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis

Obata, F., Kuranaga, E., Tomioka, K., Ming M., Takeishi, A., Chen, C., Soga, T., Miura, M.

Cell Rep. 7 ( 8 ) 821 - 833 2014.05

Research paper (scientific journal), Joint Work, Accepted

Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.

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Comparative metabolite profiling of foxglove aphids (Aulacorthum solani Kaltenbach) on leaves from resistant and susceptible soybean strains

Sato, D., Sugimoto, M., Akashi, H., Tomita, M., Soga, T.

Mol. BioSyst. 10 ( 4 ) 909 - 915 2014.04

Research paper (scientific journal), Joint Work, Accepted

Aphid infestations can cause severe decreases in soybean (Glycine max [L.] Merr.) yield. Since planting aphid-resistant soybean strains is a promising approach for pest control, understanding the resistance mechanisms employed by aphids is of considerable importance. We compared aphid resistance in seven soybean strains and found that strain Tohoku149 was the most resistant to the foxglove aphid, Aulacorthum solani Kaltenbach. We subsequently analyzed the metabolite profiles of aphids cultured on the leaves of resistant and susceptible soybean strains using capillary electrophoresis-time-of-flight mass spectrometry. Our findings showed that the metabolite profiles of several amino acids, glucose 6-phosphate, and components of the tricarboxylic acid cycle were similar in aphids reared on Tohoku149 leaves and in aphids maintained under conditions of starvation, suggesting that Tohoku149 is more resistant to aphid feeding. Compared to susceptible strains, we also found that two methylated metabolites, S-methylmethionine and trigonelline, were either not detected or decreased in aphids reared on Tohoku149 plants. Since these metabolites function as important sulfur transporters in phloem sap and osmoprotectants involved in salt and drought stress, respectively, aphid-resistance is considered to be related to sulfur metabolism and methylation. These results contribute to an increase in our understanding of soybean aphid resistance mechanisms at the molecular level.

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Metabolomic profiling of sodium fluoride-induced cytotoxicity in an oral squamous cell carcinoma cell line

Sakagami, H., Sugimoto, M., Tanaka, S., Onuma, H., Ota, S., Kaneko, M., Soga, T., Tomita, M.

Metabolomics 10 ( 2 ) 270 - 279 2014.04

Research paper (scientific journal), Joint Work, Accepted

Sodium fluoride (NaF) is used in dentistry as a preventive agent for dental caries because of its ability to remineralize the tooth surface and its antibacterial effect. Although one of its target molecules in bacteria is enolase, its site of action in human cells has not been identified. The aim of this study was to identify target metabolites that are coupled to NaF-induced cytotoxicity in the HSC-2 human oral squamous cell carcinoma cell line. Cell viability, membrane integrity and apoptosis induction were analyzed by MTT assay, trypan blue exclusion and caspase-3 activation, respectively. Cells were treated with a minimal cytotoxic concentration of NaF for various times and subjected to comprehensive metabolomics analysis using capillary electrophoresis-mass spectrometry. In the early stages, inhibition of the enolase reaction in glycolysis pathway was observed. This was coupled with rapid inhibition of the progression of TCA cycle. In the later stages, gradual increases in the AMP/ATP ratio (a putative marker of apoptosis) and oxidized products (e.g. GSSH, and methionine sulfoxide), and marginal changes in polyamine levels (putative marker of necrosis) were observed. This manuscript provides the new insight into the global impact of NaF on metabolic pathways in human oral squamous cell carcinoma cells.

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Differences in the fatty acid metabolism of visceral adipose tissue in postmenopausal women

Yamatani, H., Takahashi, K., Yoshida, T., Soga, T., Kurachi, H.

Menopause 21 ( 2 ) 170 - 176 2014.02

Research paper (scientific journal), Joint Work, Accepted

Objective: Visceral fat accumulation and metabolic syndrome incidence among women increase after menopause; therefore, fat metabolic changes and fat redistribution may occur according to menstrual status. The aim of our study was to clarify differences in subcutaneous and visceral adipose tissue metabolism between premenopausal and postmenopausal women, using metabolomics.
Methods: Thirty-nine (16 premenopausal and 23 postmenopausal) women were recruited through elective gynecologic surgery, and both subcutaneous and visceral adipose tissues were collected during surgical operation. Metabolite profiling of adipose tissue was performed by capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry.
Results: Sedoheptulose 7-phosphate, a midproduct of the pentose phosphate pathway, was significantly higher (P < 0.05) in visceral adipose tissues of premenopausal women. Dihydroxyacetone phosphate and fructose-1,6-biphosphate, midproducts of glycolysis, were significantly higher (P < 0.05) in subcutaneous adipose tissues of postmenopausal women. The concentrations of fatty acid metabolites-heptanoate (C7:0; premenopausal vs postmenopausal, 4.07 [0.72] vs 2.64 [0.28] nmol/g), octanoate (C8:0; 3.52 [0.29] vs 5.20 [0.29] nmol/g), and pelargonate (C9:0; 8.03 [0.49] vs 10.66 [0.44] nmol/g)-in the visceral fat (but not in subcutaneous fat) of postmenopausal women were significantly higher (P < 0.05) than those in the visceral fat of premenopausal women.
Conclusions: Fatty acid metabolites increase in visceral fat (but not in subcutaneous fat) after menopause. The change in fatty acid metabolism in visceral adipose tissues might be related to metabolic syndrome in postmenopausal women.

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Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol

Cheng, K., Lee, B., Masuda, T., Ito, T., Ikeda, K., Hirayama, A., Deng, L., Dong, J., Shimizu, K., Soga, T., Tomita, M., Palsson, B. O. & Robert, M.

Nat. Commun. 5 3233 2014.01

Research paper (scientific journal), Joint Work

Comparative whole-genome sequencing enables the identification of specific mutations during adaptation of bacteria to new environments and allelic replacement can establish their causality. However, the mechanisms of action are hard to decipher and little has been achieved for epistatic mutations, especially at the metabolic level. Here we show that a strain of Escherichia coli carrying mutations in the rpoC and glpK genes, derived from adaptation in glycerol, uses two distinct metabolic strategies to gain growth advantage. A 27-bp deletion in the rpoC gene first increases metabolic efficiency. Then, a point mutation in the glpK gene promotes growth by improving glycerol utilization but results in increased carbon wasting as overflow metabolism. In a strain carrying both mutations, these contrasting carbon/energy saving and wasting mechanisms work together to give an 89% increase in growth rate. This study provides insight into metabolic reprogramming during adaptive laboratory evolution for fast cellular growth.

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Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress

Kimura, T., Takahashi, A., Takabatake, Y., Namba, T, Yamamoto, T., Kaimori, J.Y., Matsui, I., Kitamura, H., Niimura, F., Matsusaka T., Soga, T., Rakugi, H., *Isaka, Y.

Autophagy 9 ( 11 ) 1876 - 1886 2013.11

Joint Work, Accepted

Chronic metabolic stress is related to diseases, whereas autophagy supplies nutrients by recycling the degradative products. Cyclosporin A (CsA), a frequently used immunosuppressant, induces metabolic stress via effects on mitochondrial respiration, and thereby, its chronic usage is often limited. Here we show that autophagy plays a protective role against CsA-induced metabolic stress in kidney proximal tubule epithelial cells. Autophagy deficiency leads to decreased mitochondrial membrane potential, which coincides with metabolic abnormalities as characterized by decreased levels of amino acids, increased tricarboxylic acid (TCA) ratio (the levels of intermediates of the latter part of the TCA cycle, over levels of intermediates in the earlier part), and decreased products of oxidative phosphorylation (ATP). In addition to the altered profile of amino acids, CsA decreased the hyperpolarization of mitochondria with the disturbance of mitochondrial energy metabolism in autophagy-competent cells, i.e., increased TCA ratio and worsening of the NAD(+)/NADH ratio, coupled with decreased energy status, which suggests that adaptation to CsA employs autophagy to supply electron donors from amino acids via intermediates of the latter part of the TCA cycle. The TCA ratio of autophagy-deficient cells was further worsened with decreased levels of amino acids in response to CsA, and, as a result, the deficiency of autophagy failed to adapt to the CsA-induced metabolic stress. Deterioration of the TCA ratio further worsened energy status. The CsA-induced metabolic stress also activated regulatory genes of metabolism and apoptotic signals, whose expressions were accelerated in autophagy-deficient cells. These data provide new perspectives on autophagy in conditions of chronic metabolic stress in disease.

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Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin: A metabolomics analysis

Saito, T., Sugimoto, M., Igarashi, K., Saito, K., Shao, L., Katsumi, T., Tomita, K., Sato, C., Okumoto, K., Nishise, Y., Watanabe, H., Tomita, M., Ueno, Y., Soga, T.

Metabolism 62 ( 11 ) 1577 - 1586 2013.11

Joint Work, Accepted

Objectives: Serum samples from patients with chronic hepatitis C were subjected to metabolomics analysis to clarify the pretreatment characteristics of their metabolites and also changes in specific metabolites resulting from antiviral therapy with pegylated interferon plus ribavirin (PegIFN/RBV).
Materials/methods: The serum levels of low-molecular-weight metabolites in the twenty patients before and 24weeks after completion of PegIFN/RBV therapy were analyzed using capillary electrophoresis and liquid chromatography-mass spectrometry.
Results: Ten patients showed a non-virological response (NVR) and 10 achieved a sustained virological response (SVR) with eradication of viremia. The pretreatment levels of tryptophan were significantly higher in the patients of SVR than in those of NVR (p=0.010). The area under the curve (AUC) value of tryptophan calculated from the receiver operating characteristic (ROC) curve for discriminating SVR from NVR was 0.84 (95% confidential interval, 0.66-1.02, p=0.010). The ROC curve of multiple logistic regression model incorporating the pretreatment levels of tryptophan and γ-glutamate-arginine showed that the AUC value was highly significant (AUC=0.92, 95% confidential interval, 0.79-1.05, p=0.002). Twenty four weeks after completion of treatment, the levels of γ-glutamyl dipeptides, glutamic acid, 5-oxoproline, glucosamine and methionine sulfoxide were decreased, whereas those of 5-methoxy-3-indoleacetate, glutamine, kynurenine and lysine were increased significantly (p<0.05) in both the NVR and SVR patients.
Conclusions: The pretreatment serum levels of certain metabolites including tryptophan are associated with the response to PegIFN/RBV therapy. PegIFN/RBV therapy can ameliorate the oxidative stress responsible for glutathione metabolism.

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Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients

Tsuruoka, M., Hara, J., Hirayama, A., Sugimoto, M., Soga, T., Shankle, W.R., Tomita , M.

Electrophoresis 34 ( 19 ) 2865 - 2872 2013.10

Research paper (scientific journal), Joint Work, Accepted

Despite increasing global prevalence, the precise pathogenesis and terms for objective diagnosis of neurodegenerative dementias remain controversial, and comprehensive understanding of the disease remains lacking. Here, we conducted metabolomic analysis of serum and saliva obtained from patients with neurodegenerative dementias (n = 10), including Alzheimer's disease, frontotemporal lobe dementia, and Lewy body disease, as well as from age-matched healthy controls (n = 9). Using CE-TOF-MS, six metabolites in serum (β-alanine, creatinine, hydroxyproline, glutamine, iso-citrate, and cytidine) and two in saliva (arginine and tyrosine) were significantly different between dementias and controls. Using multivariate analysis, serum was confirmed as a more efficient biological fluid for diagnosis compared to saliva; additionally, 45 metabolites in total were identified as candidate markers that could discriminate at least one pair of diagnostic groups from the healthy control group. These metabolites possibly provide an objective method for diagnosing dementia-type by multiphase screening. Moreover, diagnostic-type-dependent differences were observed in several tricarboxylic acid cycle compounds detected in serum, indicating that some pathways in glucose metabolism may be altered in dementia patients. This pilot study revealed novel alterations in metabolomic profiles between various neurodegenerative dementias, which would contribute to etiological investigations.

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Metabolome analysis of erythrocytes from patients with chronic hepatitis C reveals the etiology of ribavirin-induced hemolysis

Karasawa, T., *Saito, T., Ueno, Y., Sugimoto, M., Soga, T.

Int J Med Sci. 10 ( 11 ) 1575 - 1577 2013.09

Research paper (scientific journal), Joint Work, Accepted

Ribavirin is one of the major agents used in combination therapy with interferon for chronic hepatitis C, but is often associated with hemolytic anemia as a serious adverse event. Employing metabolome analysis, we demonstrated that the concentrations of intermediate metabolites produced by glycolysis and the pentose phosphate cycle in patients' erythrocytes were significantly decreased after administration of ribavirin. Our findings suggest that hemolysis associated with ribavirin is triggered by an energy crisis and consequent oxidative stress, thus having implications for the prevention of such hemolysis.

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Oncometabolites: linking altered metabolism with cancer

Yang, M., Soga, T., *Pollard, P. J.

J. Clin. Invest. 123 ( 9 ) 3652 - 3658 2013.09

Research paper (scientific journal), Joint Work, Accepted

The discovery of cancer-associated mutations in genes encoding key metabolic enzymes has provided a direct link between altered metabolism and cancer. Advances in mass spectrometry and nuclear magnetic resonance technologies have facilitated high-resolution metabolite profiling of cells and tumors and identified the accumulation of metabolites associated with specific gene defects. Here we review the potential roles of such "oncometabolites" in tumor evolution and as clinical biomarkers for the detection of cancers characterized by metabolic dysregulation.

Time-resolved metabolomics of a novel trebouxiophycean alga using 13CO2 feeding

Ito, T., Sugimoto, M., Toya, Y., Ano, Y., Kurano, N., Soga, T., Tomita, M.

J Biosci Bioeng. 116 ( 3 ) 408 - 415 2013.09

Research paper (scientific journal), Joint Work, Accepted

Oil-rich algae are potentially promising as next-generation biofuel feedstock. However, the productivity of oil needs to be improved for industrial use. The biosynthesis of oil and its control mechanism have not been characterized in any algae, and understanding the metabolic network is vital to achieve the precise engineering of algae metabolic pathways. "Pseudochoricystis ellipsoidea" MBIC 11204, a novel microalgal strain, accumulates a large amount of lipids in nitrogen-deficient conditions. In this study, "P. ellipsoidea" was grown in flat flasks with continuous illumination and aeration with 1% CO2 at 25°C. During the exponential growth phase, CO2 was switched to (13)C-labeled CO2 and samples were collected for time-course experiments. Seventy-eight pairs of unlabeled and uniformly (13)C-labeled metabolites were quantified using a capillary electrophoresis- and liquid chromatography-mass spectrometry for ionic primary metabolites and lipids, respectively. The (13)C-exchange indices of the metabolites were calculated from a concentration of unlabeled and uniformly-labeled metabolites. A hierarchical clustering analysis of the dynamics of the indices revealed 4 characteristic clusters, two of which represented rapidly-labeled metabolites, mainly composed of primary metabolites, while the two other clusters represented slowly-labeled metabolites, mainly composed of lipids. Moreover, the labeling order of these clusters was mainly matched to the metabolic process of Chlamydomonas reinhardtii, a model organism of green algae. In TCA cycle, anomalistically different of the labeling order was found. To the author's knowledge, this study for the first time in literature, characterize the features of global metabolism in "P. ellipsoidea."

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Dynamic Simulation and Metabolome Analysis of Long-Term Erythrocyte Storage in Adenine–Guanosine Solution

Nishino, T., *Yachie-Kinoshita, A., Hirayama, A., Soga, T., Suematsu, M., Tomita, M.

PLoS ONE 8 ( 8 ) e71060 2013.08

Joint Work, Accepted

Although intraerythrocytic ATP and 2,3-bisphophoglycerate (2,3-BPG) are known as direct indicators of the viability of preserved red blood cells and the efficiency of post-transfusion oxygen delivery, no current blood storage method in practical use has succeeded in maintaining both these metabolites at high levels for long periods. In this study, we constructed a mathematical kinetic model of comprehensive metabolism in red blood cells stored in a recently developed blood storage solution containing adenine and guanosine, which can maintain both ATP and 2,3-BPG. The predicted dynamics of metabolic intermediates in glycolysis, the pentose phosphate pathway, and purine salvage pathway were consistent with time-series metabolome data measured with capillary electrophoresis time-of-flight mass spectrometry over 5 weeks of storage. From the analysis of the simulation model, the metabolic roles and fates of the 2 major additives were illustrated: (1) adenine could enlarge the adenylate pool, which maintains constant ATP levels throughout the storage period and leads to production of metabolic waste, including hypoxanthine; (2) adenine also induces the consumption of ribose phosphates, which results in 2,3-BPG reduction, while (3) guanosine is converted to ribose phosphates, which can boost the activity of upper glycolysis and result in the efficient production of ATP and 2,3-BPG. This is the first attempt to clarify the underlying metabolic mechanism for maintaining levels of both ATP and 2,3-BPG in stored red blood cells with in silico analysis, as well as to analyze the trade-off and the interlock phenomena between the benefits and possible side effects of the storage-solution additives.

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Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart

Shimura, D., Nakai, G., Jiao, Q., Osanai, K., Kashikura, K., Endo, K., Soga, T., Goda, N., Minamisawa, S.

Am J Physiol Heart Circ Physiol. 305 ( 4 ) H494 - 505 2013.08

Research paper (scientific journal), Joint Work, Accepted

Energy of the cardiac muscle largely depends on fatty acid oxidation. It is known that the atrium and ventricle have chamber-specific functions, structures, gene expressions, and pathologies. The left ventricle works as a high-pressure chamber to pump blood toward the body, and its muscle wall is thicker than those of the other chambers, suggesting that energy utilization in each of the chambers should be different. However, a chamber-specific pattern of metabolism remains incompletely understood. Recently, innovative techniques have enabled the comprehensive analysis of metabolites. Therefore, we aimed to clarify differences in metabolic patterns among the chambers. Male C57BL6 mice at 6 wk old were subject to a comprehensive measurement of metabolites in the atria and ventricles by capillary electrophoresis and mass spectrometry. We found that overall metabolic profiles, including nucleotides and amino acids, were similar between the right and left ventricles. On the other hand, the atria exhibited a distinct metabolic pattern from those of the ventricles. Importantly, the high-energy phosphate pool (the total concentration of ATP, ADP, and AMP) was higher in both ventricles. In addition, the levels of lactate, acetyl CoA, and tricarboxylic acid cycle contents were higher in the ventricles. Accordingly, the activities and/or expression levels of key enzymes were higher in the ventricles to produce more energy. The present study provides a basis for understanding the chamber-specific metabolism underlining pathophysiology in the heart.

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Persistent Overexpression of Phosphoglycerate Mutase, a Glycolytic Enzyme, Modifies Energy Metabolism and Reduces Stress Resistance of Heart in Mice

Okuda, J., Niizuma, S., Shioi, T., Kato, T., Inuzuka, Y., Kawashima, T., Tamaki, Y., Kawamoto, A., Tanada, Y., Iwanaga, Y., Narazaki, M., Matsuda, T., Adachi, S., Soga, T., Takemura, G., Kondoh, H., Kita, T., Kimura, T.

PLoS ONE 8 ( 8 ) e72173 2013.08

Research paper (scientific journal), Joint Work, Accepted

Background: Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function.
Methods and results: Transgenic mice constitutively overexpressing Pgam2 in a heart-specific manner were generated, and cardiac energy metabolism and function were analyzed. Cardiac function at rest was normal. The uptake of analogs of glucose or fatty acids and the phosphocreatine/βATP ratio at rest were normal. A comprehensive metabolomic analysis revealed an increase in the levels of a few metabolites immediately upstream and downstream of Pgam2 in the glycolytic pathway, whereas the levels of metabolites in the initial few steps of glycolysis and lactate remained unchanged. The levels of metabolites in the tricarboxylic acid (TCA) cycle were altered. The capacity for respiration by isolated mitochondria in vitro was decreased, and that for the generation of reactive oxygen species (ROS) in vitro was increased. Impaired cardiac function was observed in response to dobutamine. Mice developed systolic dysfunction upon pressure overload.
Conclusions: Constitutive overexpression of Pgam2 modified energy metabolism and reduced stress resistance of heart in mice.

Abundant Nucleostemin Expression Supports the Undifferentiated Properties of Germ Cell Tumors

Uema, N., Ooshio, T., Harada, K., Naito, M., Naka, K., Hoshi T., Tadokoro, Y., Ohta, K., Ali, M. A.E., Katanno, M., Soga, T., Nakanuma, Y., Okuda, A., Hirao, A.

Am J Pathol. 183 ( 2 ) 592 - 603 2013.08

Research paper (scientific journal), Joint Work

Nucleostemin (NS) is a nucleolar GTP-binding protein that is involved in ribosomal biogenesis and protection of telomeres. We investigated the expression of NS in human germ cell tumors and its function in a mouse germ cell tumor model. NS was abundantly expressed in undifferentiated, but not differentiated, types of human testicular germ cell tumors. NS was expressed concomitantly with OCT3/4, a critical regulator of the undifferentiated status of pluripotent stem cells in primordial germ cells and embryonal carcinomas. To investigate the roles of NS in tumor growth in vivo, we used a mouse teratoma model. Analysis of teratomas derived from embryonic stem cells in which the NS promoter drives GFP expression showed that cells highly expressing NS were actively proliferating and exhibited the characteristics of tumor-initiating cells, including the ability to initiate and propagate tumor cells in vivo. NS-expressing cells exhibited higher levels of GTP than non-NS-expressing cells. Because NS protein is stabilized by intracellular GTP, metabolic changes may contribute to abundant NS expression in the undifferentiated cells. OCT3/4 deficiency in teratomas led to loss of NS expression, resulting in growth retardation. Finally, we found that teratomas deficient in NS lost their undifferentiated characteristics, resulting in defective tumor proliferation. These data indicate that abundant expression of NS supports the undifferentiated properties of germ cell tumors.

Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy

Maekawa, K., Hirayama, A., Iwata Y., Tajima Y., Nishimaki-Mogami T., Sugawara S., Ueno, N., Abe, H., Ishikawa M., Murayama M., Matsuzawa Y., Nakanishi H., Ikeda K., Arita M., Taguchi, R., Minamino N., Wakabayashi, S., Soga T. *, Saito, Y.*

J. Mol. Cell. Cardiol. 59 76 - 85 2013.06

Research paper (scientific journal), Joint Work, Accepted

Dilated cardiomyopathy (DCM), a common cause of heart failure, is characterized by cardiac dilation and reduced left ventricular ejection fraction, but the underlying mechanisms remain unclear. To investigate the mechanistic basis, we performed global metabolomic analysis of myocardial tissues from the left ventricles of J2N-k cardiomyopathic hamsters. This model exhibits symptoms similar to those of human DCM, owing to the deletion of the δ-sarcoglycan gene. Charged and lipid metabolites were measured by capillary electrophoresis mass spectrometry (MS) and liquid chromatography MS(/MS), respectively, and J2N-k hamsters were compared with J2N-n healthy controls at 4 (presymptomatic phase) and 16weeks (symptomatic) of age. Disturbances in membrane phospholipid homeostasis were initiated during the presymptomatic phase. Significantly different levels of charged metabolites, occurring mainly in the symptomatic phase, were mapped to primary metabolic pathways. Reduced levels of metabolites in glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, together with large decreases in major triacylglycerol levels, suggested that decreased energy production leads to cardiac contractile dysfunction in the symptomatic phase. A mild reduction in glutathione and a compensatory increase in ophthalmate levels suggest increased oxidative stress in diseased tissues, which was confirmed by histochemical staining. Increased levels of 4 eicosanoids, including prostaglandin (PG) E2 and 6-keto-PGF1α, in the symptomatic phase suggested activation of the protective response pathways. These results provide mechanistic insights into DCM pathogenesis and may help identify new targets for therapeutic intervention and diagnosis.

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Metabolome profiling of floral scent production in Petunia axillaris

Oyama-Okubo, N., Sakai , T., Ando, T., Nakayama, M., Soga, T.

Phytochemistry 90 37 - 42 2013.06

Research paper (scientific journal), Joint Work, Accepted

Emission of floral scent benzenoid/phenylpropanoid compounds in Petunia axillaris increases significantly at night, a change that is primarily determined by the endogenous concentration of these compounds in the corolla. Among wild type P. axillaris plants, there are lines that emit different amounts of scent. To understand how the nocturnal rhythm of floral scent concentrations is controlled, the concentration profiles of metabolites in the scent biosynthetic pathway in two lines of P. axillaris, a strongly scented line and a weakly scented line, are reported. In the strongly scented line, the concentration of a series of compounds from glucose-6-phosphate (G6P) to the scent compounds changed synchronously. In the weakly scented lines, the concentrations of some metabolites including 6-phosphogluconate (6PG) and downstream metabolites of shikimic acid were remarkably lower, suggesting a reduction in metabolism of G6P to 6PG and the metabolism of shikimic acid in the weakly scented line. Nocturnal increases in the concentrations of sucrose, fructose, and glucose were not found in strongly scented line. Nocturnal increases in concentrations of S-adenosylhomocysteine (SAH) and methionine and reductions in the concentrations of S-adenosylmethionine (SAM), a methylation donor to benzenoid-skeletons, were observed only in strongly scented line. It is concluded that the biosynthetic regulation of each step from G6P to the volatile scent benzenoids is performed by, at least in part, concentrations of substrates, and the regulation also affects concentrations of SAM cycle compounds.

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A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia

Adam, J., Yang, M., Bauerschmidt, C., Kitagawa, M., O’Flaherty, L., Maheswaran, P., O¨ zkan, G., Sahgal, N., Baban, D., Kato, K., Saito, K., Iino, K., Igarashi, K., Stratford, M., Pugh, C., Tenant, D.A., Ludwig, C., Davies, B., Ratcliffe, P. J., El-Bahrawy, M., Ashrafian, H., Soga, T., *Pollard, P. J.

Cell Rep. 3 ( 5 ) 1440 - 1448 2013.05

Research paper (scientific journal), Joint Work, Accepted

The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.

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The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns

Noguchi, R., Kubota, H., Yugi, K., Toyoshima, Y., Komori, Y., Soga, T., Kuroda, S.

Mol Syst Biol. 9 664 2013.05

Research paper (scientific journal), Joint Work, Accepted

Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC(ex)). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC(ex) was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin.

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