担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Mitochondrial morphology and function change dynamically in response to intracellular signaling and the surrounding environment. The mitochondrial fission factor Mff, which localizes to the outer mitochondrial membrane, mediates not only mitochondrial fission by recruiting the dynamin-related GTPase Drp1 to mitochondrial fission sites but also the double-stranded RNA-induced antiviral response on mitochondria through mitochondrial antiviral signaling (MAVS). Mff is reported to be regulated by AMP-activated protein kinase (AMPK)-mediated protein phosphorylation and alternative pre-mRNA splicing; however, the relationships among RNA splicing, phosphorylation, and multiple functions of Mff have not been fully understood. Here, we showed that mouse Mff has a tissue-specific splicing pattern, and at least eight Mff splice isoforms were expressed in mouse embryonic fibroblasts (MEFs). We introduced single Mff isoforms into Mff knockout MEFs and found that insertion of exon 6 just after the phosphorylation site, by the alternative splicing, reduced its phosphorylation by AMPK and its functions in mitochondrial fission and the antiviral response. In addition, the underlying mechanism repressing these functions was independent of phosphorylation. These results indicate that multiple functions of Mff on mitochondria are regulated by AMPK-mediated phosphorylation and alternative splicing, under the control of energy metabolism and cellular differentiation.

DOI： 10.1016/j.phrs.2024.107414

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

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.

DOI： 10.1007/s00125-021-05488-2

PubMed

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その他リンク： https://link.springer.com/article/10.1007/s00125-021-05488-2/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

DOI： 10.1038/s42003-021-02413-6

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その他リンク： http://www.nature.com/articles/s42003-021-02413-6

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mitochondria are multifunctional organelles that produce energy and are critical for various signaling pathways. Mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein essential for the anti-RNA viral immune response, which is regulated by mitochondrial dynamics and energetics; however, the molecular link between mitochondrial metabolism and immunity is unclear. Here we show in cultured mammalian cells that MAVS is activated by mitochondrial fission factor (Mff), which senses mitochondrial energy status. Mff mediates the formation of active MAVS clusters on mitochondria, independent of mitochondrial fission and dynamin-related protein 1. Under mitochondrial dysfunction, Mff is phosphorylated by the cellular energy sensor AMP-activated protein kinase (AMPK), leading to the disorganization of MAVS clusters and repression of the acute antiviral response. Mff also contributes to immune tolerance during chronic infection by disrupting the mitochondrial MAVS clusters. Taken together, Mff has a critical function in MAVS-mediated innate immunity, by sensing mitochondrial energy metabolism via AMPK signaling.

DOI： 10.1038/s41467-020-19287-7

PubMed

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その他リンク： https://www.nature.com/articles/s41467-020-19287-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs.

Methods: After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85 years; 54% female) were retrospectively analyzed.

Results: Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P < 0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab).

Conclusions: Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.

DOI： 10.1186/s12902-018-0267-x

Scopus

PubMed

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その他リンク： https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-018-0267-x

担当区分：筆頭著者  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：(公社)日本生化学会  

ミトコンドリアは細胞内で活発に融合と分裂を繰り返す.この形態変化および制御因子群はミトコンドリアの機能維持・品質管理や細胞応答に重要である.ミトコンドリア外膜には,感染したRNAウイルスに応答するタンパク質MAVSが局在するが,酸素呼吸によりエネルギーを作るミトコンドリアがなぜ抗ウイルス応答制御にも関与するのか,その理由はわかっていなかった.最近我々は,ミトコンドリア分裂に働くミトコンドリア外膜タンパク質Mffを解析したところ,MAVSの機能を調整しウイルス感染応答を制御する重要な役割を果たすことを見いだした.さらに,ミトコンドリアのエネルギー産生が低下すると,AMPKによりMffがリン酸化され,その結果抗ウイルス応答が抑制されることがわかった.ミトコンドリア外膜周辺で起こる栄養・代謝状態の検知・情報伝達機構の解析から,ミトコンドリアが関わるさまざまな細胞応答制御の理解が深まると期待される.(著者抄録)

DOI： 10.14952/SEIKAGAKU.2022.940230

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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開催年月日： 2023年10月30日 - 2023年11月3日

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：Suzhou  

I was selected as a chairperson of the session in this conference.

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開催年月日： 2022年6月28日 - 2022年6月30日

記述言語：英語   会議種別：ポスター発表  

開催地：タワーホール船堀  

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開催年月日： 2021年12月1日 - 2021年12月3日

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：パシフィコ横浜  

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開催年月日： 2021年11月3日 - 2021年11月5日

記述言語：日本語   会議種別：ポスター発表  

開催地：online  

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