Language：Japanese   Publisher：公益社団法人日本生化学会  

細胞小器官の一つであるミトコンドリアは，「細胞のエネルギー発電所（powerhouse）」と呼ばれる．もちろん，エネルギーとはATPのことであり，「発電所」とは内膜に存在する酸化的リン酸化システム（OXPHOS）を指すことは常識であろう．ミトコンドリアの機能を一言でまとめると「ATPをよく産生する」ことになる．しかし当然ながら，これはミトコンドリア機能の一側面にすぎない．事実，ミトコンドリアはエネルギー産生以外にも数多くの代謝反応の場として，細胞機能を維持する上できわめて重要な役割を果たしている．本稿では，ミトコンドリアを場とする「代謝」の重要性を二つのファクトから浮き彫りにし，次にその代謝経路のいくつかを点描した後，最後にその活性を「代謝産物の変動」として正確に捉えるための方法論，すなわち，ミトコンドリア-メタボロミクスについて筆者らが開発した内容の一部を解説する．

DOI： 10.14952/seikagaku.2022.940159

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Language：English   Publisher：(公社)日本生化学会  

化膿レンサ球菌ストレプトリジンO(SLO)の溶血毒素を用いた迅速分離法によるミトコンドリア(MT)標的メタボロミクスの新手法を提案した。培養HEK293細胞からのMT-SLO分離は時間・労力を節約でき、他の細胞株にも適用しえた。更に、本手法は解糖阻止薬に応答してMT-ATPの時間依存性の低下を検出でき、代謝物分析能力保有MTの調製に適していた。本手法を用いて、MT-DNA複製活性化に関連する特異的MT代謝物を探索し、ヌクレオチドとNAD+が顕著に変化していた。HEK293細胞をNAD+前駆体のβ-ニコチンアミドモノヌクレオチド(β-NMN)で処理すると、MT内のヌクレオチドが増加し、分解生成物のヌクレオシドが減少して、MT-DNA複製の速度が活性化・改善された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Cachexia, Sarcopenia and Muscle  

Background: Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T-cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease. Methods: One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time. Results: In both patient groups, methimazole-induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend <0.01). Senescent CD8+CD28−CD57+ T-cell levels in peripheral blood were positively correlated with acylcarnitine levels (P < 0.05) and decreased during thyrotoxicosis recovery (P < 0.05). High levels of senescent CD8+ T cells at Week 0 were significantly associated with small increases in handgrip strength after 12 weeks of methimazole treatment (P < 0.05), but not statistically associated with Five Times Sit to Stand Test performance. Conclusions: Restoring euthyroidism in Graves' disease patients was associated with improved skeletal muscle function and performance, while thyroid hormone-associated changes in plasma acylcarnitines levels correlated with muscle dysfunction recovery. T-cell senescence-related systemic inflammation correlated with plasma acylcarnitine levels and was also associated with small increases in handgrip strength.

DOI： 10.1002/jcsm.12889

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/diagnostics11122195

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Biochemistry  

Mitochondrial DNA (mtDNA) replication is tightly regulated and necessary for cellular homeostasis; however, its relationship with mitochondrial metabolism remains unclear. Advances in metabolomics integrated with the rapid isolation of mitochondria will allow for remarkable progress in analyzing mitochondrial metabolism. Here, we propose a novel methodology for mitochondria-targeted metabolomics, which employs a quick isolation procedure using a hemolytic toxin from Streptococcus pyogenes streptolysin O (SLO). SLO isolation of mitochondria from cultured HEK293 cells is time- and labor-saving for simultaneous multi-sample processing and has been applied to various other cell lines in this study. Furthermore, our method can detect the time-dependent reduction in mitochondrial ATP in response to a glycolytic inhibitor 2-deoxyglucose, indicating the suitability to prepare metabolite analysis-competent mitochondria. Using this methodology, we searched for specific mitochondrial metabolites associated with mtDNA replication activation, and nucleotides and NAD+ were identified to be prominently altered. Most notably, treatment of β-nicotinamide mononucleotide (β-NMN), a precursor of NAD+, to HEK293 cells activated and improved the rate of mtDNA replication by increasing nucleotides in mitochondria and decreasing their degradation products: nucleosides. Our results suggest that β-NMN metabolism plays a role in supporting mtDNA replication by maintaining the nucleotide pool balance in the mitochondria.

DOI： 10.1093/jb/mvab136

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jpsychires.2021.04.009.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jad.2020.09.118.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-75115-4.

Publisher：医歯薬出版  

DOI： 10.32118/ayu292131129

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Language：English   Publisher：Cellular and Molecular Life Sciences  

This study examines the interplay between ambient temperature, brown adipose tissue (BAT) function, and bone metabolism, emphasizing the effects of cold exposure and BAT mitochondrial activity on bone health. Utilizing ovariectomized (OVX) mice to model primary osteoporosis and BAT-specific mitochondrial dysfunction (BKO) mice, we evaluated the impact of housing temperature on bone density, immune modulation in bone marrow, and the protective role of BAT against bone loss. Cold exposure was found to universally reduce bone mass, enhance osteoclastogenesis, and alter bone marrow T-cell populations, implicating the immune system in bone remodeling under cold stress. The thermogenic function of BAT, driven by mitochondrial oxidative phosphorylation, was crucial in protecting against bone loss. Impaired BAT function, through surgical removal or mitochondrial dysfunction, exacerbated bone loss in cold environments, highlighting BAT’s metabolic role in maintaining bone health. Furthermore, cold-induced changes in BAT function led to systemic metabolic shifts, including elevated long-chain fatty acids, which influenced osteoclast differentiation and activity. These findings suggest a systemic mechanism connecting environmental temperature and BAT metabolism with bone physiology, providing new insights into the metabolic and environmental determinants of bone health. Future research could lead to novel bone disease therapies targeting these pathways.

DOI： 10.1007/s00018-024-05347-4

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DOI： 10.1186/s40170-024-00364-0

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1543209468

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DOI： 10.1681/ASN.2024m7486fkc

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Language：English   Publisher：Genes to Cells  

An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth.

DOI： 10.1111/gtc.13142

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Language：English   Publisher：DMM Disease Models and Mechanisms  

Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g (encoded by Eif4g1), Pabpc1 and Fmrp (encoded by Fmr1), in mouse Neuro2a cells. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C variant of human ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 (encoded by Rps6) and increased susceptibility to heat stress. In agreement with these findings, induced pluripotent stem cells (iPSCs) from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient-derived iPSCs showed lower calcium influxes in responses to stimulation with ATP than those in control iPSCs. These data indicate that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes in patients with the p.R756C variant among a variety of ATP1A3-related disorders.

DOI： 10.1242/dmm.050574

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Language：English   Publisher：Bioscience reports  

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

DOI： 10.1042/BSR20231992

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Language：English   Publisher：International Journal of Molecular Sciences  

Pancreatic ductal adenocarcinoma (PDAC) is a solid-tumor malignancy. To enhance the treatment landscape of PDAC, a 3D model optimized for rigorous drug screening is essential. Within the PDAC tumor microenvironment, a dense stroma comprising a large extracellular matrix and cancer-associated fibroblasts (CAFs) is well-known for its vital role in modulating tumor growth, cellular heterogeneity, bidirectional paracrine signaling, and chemoresistance. In this study, we employed a fibroblast-populated collagen lattice (FPCL) modeling approach that has the ability to replicate fibroblast contractility in the collagenous matrix to build dense stroma. This FPCL model allows CAF differentiation by facilitating multifaceted cell–cell interactions between cancer cells and CAFs, with the differentiation further influenced by mechanical forces and hypoxia carried within the 3D structure. Our FPCL models displayed hallmark features, including ductal gland structures and differentiated CAFs with spindle shapes. Through morphological explorations alongside in-depth transcriptomic and metabolomic profiling, we identified substantial molecular shifts from the nascent to mature model stages and potential metabolic biomarkers, such as proline. The initial pharmacological assays highlighted the effectiveness of our FPCL model in screening for improved therapeutic strategies. In conclusion, our PDAC modeling platform mirrors complex tumor microenvironmental dynamics and offers an unparalleled perspective for therapeutic exploration.

DOI： 10.3390/ijms25073740

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1405207185

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Language：English   Publisher：Bioengineering  

Pancreatic ductal adenocarcinoma (PDAC) is a refractory tumor with a poor prognosis, and its complex microenvironment is characterized by a fibrous interstitial matrix surrounding PDAC cells. Type I collagen is a major component of this interstitial matrix. Abundant type I collagen promotes its deposition and cross-linking to form a rigid and dense physical barrier, which limits drug penetration and immune cell infiltration and provides drug resistance and metabolic adaptations. In this study, to identify the physical effect of the stroma, type I collagen was used as a 3D matrix to culture Capan-1 cells and generate a 3D PDAC model. Using transcriptome analysis, a link between type I collagen-induced physical effects and the promotion of Capan-1 cell proliferation and migration was determined. Moreover, metabolomic analysis revealed that the physical effect caused a shift in metabolism toward a glycolytic phenotype. In particular, the high expression of proline in the metabolites suggests the ability to maintain Capan-1 cell proliferation under hypoxic and nutrient-depleted conditions. In conclusion, we identified type I collagen-induced physical effects in promoting Capan-1 cells, which cause PDAC progression, providing support for the role of dense stroma in the PDAC microenvironment and identifying a fundamental method for modeling the complex PDAC microenvironment.

DOI： 10.3390/bioengineering10121437

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Language：English   Publisher：Life Science Alliance  

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

DOI： 10.26508/lsa.202302116

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Language：English   Publisher：Nucleic Acids Research  

The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.

DOI： 10.1093/nar/gkad591

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Language：English   Publisher：JACC: Basic to Translational Science  

Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.

DOI： 10.1016/j.jacbts.2023.02.014

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Language：English   Publisher：エルゼビア・ジャパン(株)  

マウスの生後早期の視床機能の発達におけるShank3a/bアイソフォームの役割について検討した。WTマウスとShank3a/bノックアウトを使用した。評価項目は脳の各領域における定量PCR、カイニン酸治療、免疫蛍光染色、ウェスタンブロット法などとした。その結果、マウスShank3スプライシングアイソフォームShank3a/bは視床核で特異的に発現し、生後2～4週間でピークに達することが示された。また、Shank3a/bノックアウトマウスでは視床核のパルブアルブミンが低かった。一貫して、Shank3a/bノックアウトマウスは、カイニン酸処理後、WTマウスと比較して全般発作を起こしやすいことが示された。以上から、Shank3a/bのNT-Ankドメインは、マウス生後早期において、視床皮質ニューロンを過剰興奮から守る分子経路を制御していることが示された。

Language：English   Publisher：International Journal of Molecular Sciences  

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, largely due to its unique tumor microenvironment (TME) and dense fibrotic stroma. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor growth and metastasis, contributing to the metabolic adaptation of PDAC cells. However, the metabolic interactions between PDAC cells and CAFs are not well-understood. In this study, an in vitro co-culture model was used to investigate these metabolic interactions. Metabolomic analysis was performed under monoculture conditions of Capan−1 PDAC cells and CAF precursor cells, as well as co-culture conditions of PDAC cells and differentiated inflammatory CAF (iCAF). Co-cultured Capan−1 cells displayed significant metabolic changes, such as increased 2-oxoglutaric acid and lauric acid and decreased amino acids. The metabolic profiles of co-cultured Capan−1 and CAFs revealed differences in intracellular metabolites. Analysis of extracellular metabolites in the culture supernatant showed distinct differences between Capan−1 and CAF precursors, with the co-culture supernatant exhibiting the most significant changes. A comparison of the culture supernatants of Capan−1 and CAF precursors revealed different metabolic processes while co-culturing the two cell types demonstrated potential metabolic interactions. In conclusion, this study emphasizes the importance of metabolic interactions between cancer cells and CAFs in tumor progression and highlights the role of TME in metabolic reprogramming.

DOI： 10.3390/ijms241311015

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences of the United States of America  

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

DOI： 10.1073/pnas.2203628119

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Neuroscience Research  

Epileptic seizures are distinct but frequent comorbidities in children with autism spectrum disorder (ASD). The hyperexcitability of cortical and subcortical neurons appears to be involved in both phenotypes. However, little information is available concerning which genes are involved and how they regulate the excitability of the thalamocortical network. In this study, we investigate whether an ASD-associated gene, SH3 and multiple ankyrin repeat domains 3 (Shank3), plays a unique role in the postnatal development of thalamocortical neurons. We herein report that Shank3a/b, the splicing isoforms of mouse Shank3, were uniquely expressed in the thalamic nuclei, peaking from two to four weeks after birth. Shank3a/b-knockout mice showed lower parvalbumin signals in the thalamic nuclei. Consistently, Shank3a/b-knockout mice were more susceptible to generalized seizures than wild-type mice after kainic acid treatments. Together, these data indicate that NT-Ank domain of Shank3a/b regulates molecular pathways that protect thalamocortical neurons from hyperexcitability during the early postnatal period of mice.

DOI： 10.1016/j.neures.2023.03.001

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Communications Biology  

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor developed, has been shown to reduce cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Several studies have suggested that empagliflozin improves the cardiac energy state which is a partial cause of its potency. However, the detailed mechanism remains unclear. To address this issue, we used a mouse model that enabled direct measurement of cytosolic and mitochondrial ATP levels. Empagliflozin treatment significantly increased cytosolic and mitochondrial ATP levels in the hearts of db/db mice. Empagliflozin also enhanced cardiac robustness by maintaining intracellular ATP levels and the recovery capacity in the infarcted area during ischemic-reperfusion. Our findings suggest that empagliflozin enters cardiac mitochondria and directly causes these effects by increasing mitochondrial ATP via inhibition of NHE1 and Nav1.5 or their common downstream sites. These cardioprotective effects may be involved in the beneficial effects on heart failure seen in clinical trials.

DOI： 10.1038/s42003-023-04663-y

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：eNeuro  

Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.

DOI： 10.1523/ENEURO.0353-22.2023

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Language：Japanese   Publisher：Japanese Society of Biological Psychiatry  

Patients with mental disorders rarely visit psychiatrists from the early stages of illness, which tends to delay the introduction of appropriate medical care. On the other hand, it is not uncommon for these patients to visit non‐psychiatric physicians for their physical symptoms. Therefore, development of biomarkers by blood sampling that can be performed outside of psychiatry will lead to early detection and intervention of mental disorders. With this expectation, we are searching for objective blood biomarkers of mental disorders.
We herein introduce about blood metabolome analysis and present our recent studies focusing on depression and hikikomori (pathological social withdrawal) . We have found significant associations between depressive severity and 3‐hydroxybutyrate, suicidal ideation and kynurenine metabolites, and hikikomori and acylcarnitine/arginine. Establishment of objective biological evaluation systems for mental disorders is expected to lead to the realization of early detection and intervention of mental disorders as well as to the elimination of prejudice and stigma against mental disorders.

DOI： 10.11249/jsbpjjpp.34.1_7

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：iScience  

The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.

DOI： 10.1016/j.isci.2022.104889

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Cellular and Molecular Life Sciences  

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient’s quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.

DOI： 10.1007/s00018-022-04510-z

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PubMed

Language：English   Publisher：Scientific Reports  

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

DOI： 10.1038/s41598-022-12528-3

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：大道学館出版部  

82歳女性。糖尿病に対する即効性インスリン、持効性インスリン、SGLT-2阻害薬服用中に気尿が出現した。精査結果から、本症例ではSGLT-2阻害薬による尿糖排泄量増加に伴う尿内発酵症候群が考えられ、膀胱内にはエタノール産生が確認された。SGLT-2阻害薬を一時中止したが、血糖コントロールが不安定となったため再開し、その後は慎重に経過観察しながら投与を継続している。

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fimmu.2021.714897. eCollection 2021.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s42003-021-02498-z.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.15252/embj.2020105268.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/braincomms/fcab058

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1096/fj.202001113R.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-78410-2.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-73918-z

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.isci.2020.101654.

Language：English   Publishing type：Research paper (scientific journal)  

Background: Linoleic acid is the major fatty acid moiety of cardiolipin, which is central to the assembly of components involved in mitochondrial oxidative phosphorylation (OXPHOS). Although linoleic acid is an essential nutrient, its excess intake is harmful to health. On the other hand, linoleic acid has been shown to prevent the reduction in cardiolipin content and to improve mitochondrial function in aged rats with spontaneous hypertensive heart failure (HF). In this study, we found that lower dietary intake of linoleic acid in HF patients statistically correlates with greater severity of HF, and we investigated the mechanisms therein involved. Methods: HF patients, who were classified as New York Heart Association (NYHA) functional class I (n = 45), II (n = 93), and III (n = 15), were analyzed regarding their dietary intakes of different fatty acids during the one month prior to the study. Then, using a mouse model of HF, we confirmed reduced cardiolipin levels in their cardiac myocytes, and then analyzed the mechanisms by which dietary supplementation of linoleic acid improves cardiac malfunction of mitochondria. Results: The dietary intake of linoleic acid was significantly lower in NYHA III patients, as compared to NYHA II patients. In HF model mice, both CI-based and CII-based OXPHOS activities were affected together with reduced cardiolipin levels. Silencing of CRLS1, which encodes cardiolipin synthetase, in cultured cardiomyocytes phenocopied these events. Feeding HF mice with linoleic acid improved both CI-based and CII-based respiration as well as left ventricular function, together with an increase in cardiolipin levels. However, although assembly of the respirasome (i.e., CI/CIII₂/CIV complex), as well as assembly of CII subunits and the CIII₂/CIV complex statistically correlated with cardiolipin levels in cultured cardiomyocytes, respirasome assembly was not notably restored by dietary linoleic acid in HF mice. Therefore, although linoleic acid may significantly improve both CI-based and CII-based respiration of cardiomyocytes, respirasomes impaired by HF were not easily repaired by the dietary intake of linoleic acid. Conclusions: Dietary supplement of linoleic acid is beneficial for improving cardiac malfunction in HF, but is unable to completely cure HF.

DOI： 10.1186/s12964-019-0445-0

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jb/mvz043

Language：English   Publishing type：Research paper (scientific journal)  

Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

DOI： 10.3389/fncel.2019.00031

Language：English   Publishing type：Research paper (scientific journal)  

Aim: Understanding premorbid personality is important, especially when considering treatment selection. Historically, the premorbid personality of patients with major depression in Japan was described as Shuchaku-kishitsu [similar to Typus melancholicus], as proposed by Shimoda in the 1930s. Since around 2000, there have been increased reports in Japan of young adults with depression who have had premorbid personality differing from the traditional type. In 2005, Tarumi termed this novel condition ‘dysthymic-type depression,’ and more recently the condition has been called Shin-gata/Gendai-gata Utsu-byo [modern-type depression (MTD)]. We recently developed a semi-structured diagnostic interview to evaluate MTD. Development of a tool that enables understanding of premorbid personality in a short time, especially at the early stage of treatment, is desirable. The object of this study was to develop a self-report scale to evaluate the traits of MTD, and to assess the scale's psychometric properties, diagnostic accuracy, and biological validity. Methods: A sample of 340 participants from clinical and community settings completed measures. Psychometric properties were assessed with factor analysis. Diagnostic accuracy of the MTD traits was compared against a semi-structured interview. Results: The questionnaire contained 22 items across three subscales, thus we termed it the 22-item Tarumi's Modern-Type Depression Trait Scale: Avoidance of Social Roles, Complaint, and Low Self-Esteem (TACS-22). Internal consistency, test–retest reliability, and convergent validity were all satisfactory. Among patients with major depression, the area under the curve was 0.757 (sensitivity of 63.1% and specificity of 82.9%) and the score was positively correlated with plasma tryptophan. Conclusion: The TACS-22 possessed adequate psychometric properties and diagnostic accuracy in an initial sample of Japanese adults. Additional research on its ability to support clinical assessment of MTD is warranted.

DOI： 10.1111/pcn.12842

Language：English   Publishing type：Research paper (scientific journal)  

Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo.

DOI： 10.1016/j.celrep.2018.10.057

Language：English   Publishing type：Research paper (scientific journal)  

Background: Early intervention in depression has been critical to prevent its negative impact including suicide. Recent blood biomarker studies for major depressive disorder (MDD) have suggested that tryptophan-kynurenine and lipid related metabolites are involved in the pathophysiology of MDD. However, there have been limited studies investigating these blood biomarkers in first-episode drug-naïve MDD, which are particularly important for early intervention in depression. Methods: As an exploratory pilot case-control study, we examined the above blood biomarkers, and analyzed how these biomarkers are associated with clinical variables in first-episode drug-naïve MDD patients, based on metabolome/lipidome analysis. Results: Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740). Lower serum high density lipoprotein-cholesterol (HDL-C) was the predictive biomarker for severity of depression in MDD group (R² = 0.444). Interestingly, depressive symptoms were variously correlated with plasma tryptophan-kynurenine and lipid related metabolites. Moreover, plasma tryptophan-kynurenine metabolites and cholesteryl esters (CEs) were significantly correlated in MDD group, but not in HC group. Limitations: This study had small sample size, and we did not use the multiple test correction. Conclusions: This is the first study to suggest that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients. The present study sheds new light on early intervention in clinical practice in depression, and further clinical studies especially large-scale prospective studies are warranted.

DOI： 10.1016/j.jad.2018.01.014

Language：English   Publishing type：Research paper (scientific journal)  

Clinical application of the major anticancer drug, cisplatin, is limited by severe side effects, especially acute kidney injury (AKI) caused by nephrotoxicity. The detailed metabolic mechanism is still largely unknown. Here, we used an integrated technique combining mass spectrometry imaging (MSI) and liquid chromatography–mass spectrometry (LC–MS) to visualize the diverse spatiotemporal metabolic dynamics in the mouse kidney after cisplatin dosing. Biological responses to cisplatin was more sensitively detected within 24 h as a metabolic alteration, which is much earlier than possible with the conventional clinical chemistry method of blood urea nitrogen (BUN) measurement. Region-specific changes (e.g., medulla and cortex) in metabolites related to DNA damage and energy generation were observed over the 72-h exposure period. Therefore, this metabolomics approach may become a novel strategy for elucidating early renal responses to cisplatin, prior to the detection of kidney damage evaluated by conventional method.

DOI： 10.1016/j.bbrc.2018.01.012

Language：English   Publishing type：Research paper (scientific journal)  

Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy.

DOI： 10.1038/s41598-017-15414-5

Language：English   Publishing type：Research paper (scientific journal)  

Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells.

DOI： 10.1038/s41598-017-14440-7

Language：English   Publishing type：Research paper (scientific journal)  

Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency.

DOI： 10.1038/s41389-017-0009-3

Language：English   Publishing type：Research paper (scientific journal)  

Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial p32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of p32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic p32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial p32/C1qbp in the heart. Methods and results We investigated the role of p32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against p32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of p32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by p32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific p32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the p32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in p32-deficient compared with control myocytes, AMPKI' was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the p32-deficient hearts. Conclusion These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.

DOI： 10.1093/cvr/cvx095

Language：English   Publishing type：Research paper (scientific journal)  

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.

DOI： 10.1371/journal.pone.0165267

Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Event date： 2021.10

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：横浜市   Country：Japan  

Event date： 2021.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2019.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2019.10

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：仙台国際センター   Country：Japan  

Event date： 2019.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本臨床衛生検査技師会館   Country：Japan  

Event date： 2019.7

Language：Japanese  

Venue：京都   Country：Japan  

Event date： 2019.2

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡県保健環境研究所   Country：Japan  

Event date： 2018.11

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Venue：横浜   Country：Japan  

Event date： 2018.10

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Venue：神戸   Country：Japan  

Event date： 2018.10

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Venue：神戸   Country：Japan  

Event date： 2018.9

Language：English   Presentation type：Oral presentation (general)  

Venue：奈良国際フォーラムIRAKA   Country：Japan  

Event date： 2018.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋国際会議場   Country：Japan  

Event date： 2018.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋国際会議場   Country：Japan  

Event date： 2018.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学医学部保健学科   Country：Japan  

Event date： 2018.6

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Venue：シアトル   Country：United States  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：九州大学稲盛財団記念館 A会議室   Country：Japan  

Event date： 2017.10

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Venue：札幌   Country：Japan  

Event date： 2017.9

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Venue：横浜   Country：Japan  

Event date： 2017.6

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Venue：ケルン   Country：Germany  

Event date： 2015.9 - 2015.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：静岡県三島市三島文化会館   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鹿児島   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.11 - 2016.12

Language：Japanese  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2016.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸国際展示場   Country：Japan  

Event date： 2015.11 - 2016.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岐阜   Country：Japan  

Event date： 2015.9 - 2015.10

Language：Japanese  

Venue：静岡県三島市三島文化会館   Country：Japan  

Event date： 2015.9 - 2015.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：静岡県三島市三島文化会館   Country：Japan  

Language：English  

Country：United Kingdom  

Language：Japanese  

Venue：神戸   Country：Japan  

Language：Japanese  

Venue：福岡   Country：Japan  

Language：Japanese  

Venue：福岡   Country：Japan  

Language：Japanese  

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞メタボローム解析は質量分析を用いて代謝物を網羅的に測定するオミクス解析の一種である。生体内の代謝物は,複雑な細胞環境の最終表現型としてさまざまな生理機能を反映しており,その経時的変化を捉えることができると考えられる。九州大学病院「気分障害ひきこもり外来」では血液メタボローム解析を用いたうつ病をはじめとする気分障害の病態解明,客観的バイオマーカー開発,治療法開発を進めている。本稿では,血液メタボローム解析について概説し,筆者らが推進している抑うつ症状・自殺などに関連した血液メタボローム解析研究とその成果を紹介する。筆者らはこれまでに抑うつ重症度に関連する3-ヒドロキシ酪酸,自殺念慮に相関するキヌレニン系代謝物,さらには性格傾向に関連するいくつかの代謝物を予備的に同定してきた。こうした研究を基にした社会実装により,うつ病を客観的に評価できるシステムが導入されることで,うつ病への早期発見・早期介入の実現が期待される。

Language：Japanese   Publisher：日本生物学的精神医学会  

うつ病など精神疾患をもつ患者が発症初期から精神医療機関を受診することはまれであり,適切な精神医療の導入は遅れがちである。他方,こうした患者は身体症状のために身体科を受診していることがまれではない。しかるに,筆者らは精神科以外でも実施可能な採血による血液バイオマーカーの開発が,精神疾患の早期発見・早期介入につながることを期待して,血液を用いた精神疾患の客観的バイオマーカー開発を進めている。本稿では,血液メタボローム解析について概説し,うつ病やひきこもりに関連した研究の成果を紹介する。筆者らはこれまで抑うつ重症度と3ヒドロキシ酪酸,自殺とキヌレニン経路代謝物,ひきこもりとアシルカルニチン/アルギニンとの関連を萌芽的に見いだしてきた。こうした研究の発展により精神疾患を採血で客観的に生物学的に評価できるシステムが構築されることで,精神疾患の早期発見・早期介入の実現に加えて精神疾患への偏見解消が期待される。(著者抄録)

Language：Japanese   Publisher：(一社)日本臨床化学会  

Language：Japanese   Publisher：(株)アークメディア  

Language：Japanese   Publisher：(一社)日本臨床化学会  

Language：Japanese   Publisher：(公社)日本生化学会  

細胞小器官の一つであるミトコンドリアは,「細胞のエネルギー発電所(powerhouse)」と呼ばれる.もちろん,エネルギーとはATPのことであり,「発電所」とは内膜に存在する酸化的リン酸化システム(OXPHOS)を指すことは常識であろう.ミトコンドリアの機能を一言でまとめると「ATPをよく産生する」ことになる.しかし当然ながら,これはミトコンドリア機能の一側面にすぎない.事実,ミトコンドリアはエネルギー産生以外にも数多くの代謝反応の場として,細胞機能を維持する上できわめて重要な役割を果たしている.本稿では,ミトコンドリアを場とする「代謝」の重要性を二つのファクトから浮き彫りにし,次にその代謝経路のいくつかを点描した後,最後にその活性を「代謝産物の変動」として正確に捉えるための方法論,すなわち,ミトコンドリア-メタボロミクスについて筆者らが開発した内容の一部を解説する.(著者抄録)

Type：Competition, symposium, etc. 

Number of participants：3,000

Type：Competition, symposium, etc. 

Number of participants：70

Type：Competition, symposium, etc. 

Number of participants：3,000

Type：Competition, symposium, etc. 

Number of participants：300

福岡県保健環境研究所主催の研究セミナーの講師を務めた
「Rで広がるデータ解析の地平」

機械学習の臨床検査応用に関する自主勉強会を主催している