Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Gotoh Kazuhito Last modified date:2021.09.10

Assistant Professor / Clinical Chemistry and Laboratory Medicine / Clinical Laboratories / Kyushu University Hospital

1. Yukina Takeichi, Takashi Miyazawa, Shohei Sakamoto, Yuki Hanada, Lixiang Wang, Kazuhito Gotoh, Keiichiro Uchida, Shunsuke Katsuhara, Ryuichi Sakamoto, Takaya Ishihara, Keiji Masuda, Naotada Ishihara, Masatoshi Nomura, Yoshihiro Ogawa, Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor., Diabetologia, 10.1007/s00125-021-05488-2, 2021.05, AIMS/HYPOTHESIS: Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. METHODS: We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. RESULTS: MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. CONCLUSIONS/INTERPRETATION: We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH..
2. Kazuhito Gotoh, Yurie Takata, Yuya Nakashima, Soichi Mizuguchi, Keishi Komori, Dongchon Kang, Metabolic analysis of mouse bone-marrow-derived dendritic cells using an extracellular flux analyzer., STAR protocols, 10.1016/j.xpro.2021.100401, 2, 2, 100401-100401, 2021.06, Dendritic cell (DC) maturation induced by Toll-like receptor (TLR) agonists requires the activation of downstream metabolic changes. Here, we provide a detailed protocol to measure glycolysis, mitochondrial respiration, and fatty acid oxidation in mouse bone-marrow-derived DCs with the Seahorse XF24 extracellular flux (XF) analyzer. XF analysis with the Seahorse bioanalyzer has become a standard method to measure bioenergetic functions in cells, and this protocol can be adapted to other immune cells. For complete information on using this protocol, please refer to Gotoh et al. (2018)..
3. Kazuhito Gotoh, Yuya Kunisaki, Soichi Mizuguchi, Daiki Setoyama, Kentaro Hosokawa, Hisayuki Yao, Yuya Nakashima, Mikako Yagi, Takeshi Uchiumi, Yuichiro Semba, Jumpei Nogami, Koichi Akashi, Fumio Arai, Dongchon Kang, Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45 TER119Erythroid and Lymphoid Progenitors, iScience, 10.1016/j.isci.2020.101654, 23, 11, 2020.11, p32/C1qbp regulates mitochondrial protein synthesis and is essential for oxidative phosphorylation in mitochondria. Although dysfunction of p32/C1qbp impairs fetal development and immune responses, its role in hematopoietic differentiation remains unclear. Here, we found that mitochondrial dysfunction affected terminal differentiation of newly identified erythroid/B-lymphoid progenitors among CD45 Ter119 CD31 triple-negative cells (TNCs) in bone marrow. Hematopoietic cell-specific genetic deletion of p32/C1qbp (p32cKO) in mice caused anemia and B-lymphopenia without reduction of hematopoietic stem/progenitor cells. In addition, p32cKO mice were susceptible to hematopoietic stress with delayed recovery from anemia. p32/C1qbp-deficient CD51 TNCs exhibited impaired mitochondrial oxidation that consequently led to inactivation of mTORC1 signaling, which is essential for erythropoiesis. These findings uncover the importance of mitochondria, especially at the stage of TNCs during erythropoiesis, suggesting that dysregulation of mitochondrial protein synthesis is a cause of anemia and B-lymphopenia with an unknown pathology..
4. Ko Igami1,2,3, Takeshi Uchiumi​1,4, Saori Ueda1, Kazuyuki Kamioka2,5, Daiki Setoyama1, Kazuhito Gotoh1, Masaru Akimoto1, Shinya Matsumoto1, Dongchon Kang1, Characterization and function of medium and large extracellular vesicles from plasma and urine by surface antigens and Annexin V, PeerJ Analytical Chemistry,, 2, e4, 2020.01.
5. Kazuhito Gotoh, Takafumi Morisaki, Daiki Setoyama, Katsuhiko Sasaki, Mikako Yagi, Ko Igami, Soichi Mizuguchi, Takeshi Uchiumi, Yoshinori Fukui, Dongchon Kang, Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation, Cell Reports,, VOLUME 25, ISSUE 7, 1800-1805, 2018.11, 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..
6. Nishikimi, Akihiko, Uruno, Takehito, Duan, Xuefeng, Cao, Qinhong, Okamura, Yuji, Saitoh, Takashi;, Saito, Nae, Sakaoka, Shunsuke, Du, Yao, Suenaga, Atsushi, Kukimoto-Niino, Mutsuko, Miyano, Kei;, Gotoh, Kazuhito, Okabe, Takayoshi, Sanematsu, Fumiyuki, Tanaka, Yoshihiko, Sumimoto, Hideki;, Honma, Teruki, Yokoyama, Shigeyuki;, Nagano, Tetsuo, Blockade of Inflammatory Responses by a Small-Molecule Inhibitor of the Rac Activator DOCK2, CHEMISTRY & BIOLOGY, 10.1016/j.chembiol.2012.03.008, 19, 4, 488-497, 2012.04.
7. Gotoh, Kazuhito, Tanaka, Yoshihiko, Nishikimi, Akihiko, Nakamura, Risa, Yamada, Hisakata, Maeda, Naoyoshi, Ishikawa, Takahiro, Hoshino, Katsuaki, Uruno, Takehito, Cao, Qinhong, Higashi, Sadayuki, Kawaguchi, Yasushi, Enjoji, Munechika, Takayanagi, Ryoichi, Kaisho, Tsuneyasu, Yoshikai, Yasunobu, Fukui, Yoshinori, Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation, JOURNAL OF EXPERIMENTAL MEDICINE, 10.1084/jem.20091776, 207, 4, 721-730, 2010.04.
8. Gotoh, Kazuhito, Tanaka, Yoshihiko, Nishikimi, Akihiko, Inayoshi, Ayumi, Enjoji, Munechika, Takayanagi, Ryoichi, Sasazuki, Takehiko, Fukui, Yoshinori, Brief report - Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells, BLOOD, 10.1182/blood-2007-09-112169, 111, 6, 2973-2976, 2008.03.
9. Tanaka, Yoshihiko, Hamano, Shinjiro, Gotoh, Kazuhito, Murata, Yuzo, Kunisaki, Yuya, Nishikimi, Akihiko, Takii, Ryosuke, Kawaguchi, Makiko, Inayoshi, Ayumi, Masuko, Sadahiko, Himeno, Kunisuke, Sasazuki, Takehiko, Fukui, Yoshinori, T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2, NATURE IMMUNOLOGY, 10.1038/ni1506, 8, 10, 1067-1075, 2007.10.
10. Niho K, Nakasya A, Ijichi A, Tsujita J, Gotoh Kazuhito, Shinozaki H, Matsumoto M, A case of bleeding duodenal ulcer with pemphigus vulgaris during steroid therapy, Clinical journal of Gastroenterology, 7, 3, 223-227, 2014.05.
11. Keisuke Monji, Takeshi Uchiumi, Saki Hoshizawa, Mikako Yagi, Takashi Matsumoto, Daiki Setoyama, Yuichi Matsushima, Kazuhito Gotoh, Rie Amamoto, Donchon Kang, Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells, ONCOTARGET, 10.18632/oncotarget.12117, 7, 46, 75221-75234, 2016.11.
12. Sasaki, Katsuhiko, Gotoh, Kazuhito, Sho Miake, Setoyama, Daiki, Yagi, Mikako, Igami, Ko, Uchiumi, Takeshi, Kang, Dongchon, p32 is Required for Appropriate Interleukin- 6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock, EBIOMEDICINE, 20, 161-172, 2017.06, Sepsis is a major cause of morbidity and mortality in seriously ill patients and mitochondrial dysfunction is associated with poor outcomes in septic patients. Although interleukin-6 (IL-6) is a good prognostic marker for sepsis, the relationship between mitochondrial dysfunction and IL-6 remains poorly understood. We identified p32/C1QBP/HABP1 as a regulator of IL-6 production in response to lipopolysaccharide (LPS). LPS induced IL-6 overproduction in p32 deficient mouse embryonic fibroblasts (MEFs) through NF-κB independent but activating transcription factor (ATF) 4 dependent pathways. Short hairpin RNA-based knockdown of ATF4 in p32 deficient MEFs markedly inhibited LPS-induced IL-6 production. Furthermore, MEFs treated with chloramphenicol, an inhibitor of mitochondrial translation, produced excessive IL-6 via ATF4 pathways. Using a LPS-induced endotoxin shock model, mice with p32 ablation in myeloid cells showed increased lethality and overproduction of IL-6. Thus, this study provides a molecular link how mitochondrial dysfunction leads to IL-6 overproduction and poor prognosis of sepsis..
13. Shigeru Matsuda, Takehiro Yasukawa, Yuriko Sakaguchi, Kenji Ichiyanagi, Motoko Unoki, Kazuhito Gotou, Kei Fukuda, Hiroyuki Sasaki, Tsutomu Suzuki, Dongchon Kang, Accurate estimation of 5-methylcytosine in mammalian mitochondrial DNA, Scientific Reports, 10.1038/s41598-018-24251-z, 8, 2018.04.
14. Akihiko Nishikimi, Takehito Uruno, Xuefeng Duan, Qinhong Cao, Yuji Okamura, Takashi Saitoh, Nae Saito, Shunsuke Sakaoka, Yao Du, Atsushi Suenaga, Mutsuko Kukimoto-Niino, Kei Miyano, Kazuhito Gotou, Takayoshi Okabe, Fumiyuki Sanematsu, Yoshihiko Tanaka, Hideki Sumimoto, Teruki Honma, Shigeyuki Yokoyama, Tetsuo Nagano, Daisuke Kohda, Motomu Kanai, Yoshinori Fukui, Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2, Cell Chemical Biology, 10.1016/j.chembiol.2012.03.008, 19, 4, 488-497, 2012.04.