Elucidation of the Common Basis of Physiological and Pathological Aging of the Heart Focusing on Mitochondrial Dynamics

• Project/Area Number: 19K16527
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Jichi Medical University (2021-2022); Tokyo University of Pharmacy and Life Science (2019)
• Principal Investigator: Tokuyama Takeshi 自治医科大学, 医学部, 助教 (30808093)
• Project Period (FY): 2021-03-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ミトコンドリアダイナミクス / 老化 / 心筋梗塞 / MITOL / MARCH5 / Drp1 / 遺伝子治療 / ミトコンドリア動態 / ユビキチンリガーゼ / 心不全 / ミトコンドリア / ミトコンドリア形態制御 / 心臓老化 / MITOL / 心疾患 / MITOL/MARCH5

Outline of Research at the Start

ミトコンドリアは個体の寿命、臓器の機能を維持する上で非常に重要な細胞内小器官である。所属研究室はミトコンドリアに局在するユビキチンリガーゼMITOLを発見した。心臓におけるMITOLの機能を解析したところ、ミトコンドリア動態が組織老化の基盤を制御している可能性を見出した。本研究は、心臓におけるMITOLの存在意義を解明し、『老化』の基盤メカニズムを明らかにすることを目的とする。具体的には、心臓におけるMITOLの重要性と、生理的・病的老化にともなうMITOLの運命・機能の解析から、心臓の組織老化を中心的に駆動するミトコンドリア動態の存在意義とその分子機構を明らかにする。

Outline of Final Research Achievements

Mitochondria regulate their shape through fission and fusion, and excessive fission can cause dysfunction and cell damage. This study explores how MITOL, a mitochondrial ubiquitin ligase, controls mitochondrial morphology by degrading the fission factor Drp1. Using mice with MITOL deletion in cardiomyocytes, we observed phenotypes of cardiac aging. Additionally, Drp1 inhibition alleviated cellular senescence related to MITOL reduction. These results suggest that impaired MITOL function can lead to abnormal mitochondrial morphology and accelerated aging, shedding light on the mechanisms behind mitochondrial morphology and aging.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会の到来により加齢性疾患の根治が大きな問題となっている。哺乳類の老化の基本メカニズムは未だ不明瞭なところが多く、これらを生物学的根拠に基づいて明らかにし、老化回避の方策を開発することが必要である。本研究では「生理的老化」と「病的老化」の双方において、新しくミトコンドリアユビキチンリガーゼMITOLの機能低下がその上流に存在することを示した。また、ミトコンドリア形態調節がこれらの老化基盤を作ることを明らかにした。この成果は、新規にMITOLという分子が形態調節を通じて組織老化に関与すること、ミトコンドリアの形態異常は老化の病態基盤である可能性を示唆することに繋がり有益な知見となりうる。

Research Products

• [Journal Article] Total and reduced/oxidized forms of coenzyme Q10 in fibroblasts of patients with mitochondrial disease (2023)
  • Author(s): Watanabe, C., Osaka, H., Watanabe, M., Miyauchi, A., Jimbo, E. F., Tokuyama, T., Uosaki, H., Kishita, Y., Okazaki, Y., Onuki, T., Ebihara, T., Aizawa, K., Murayama, K., Ohtake, A., & Yamagata, T.
  • Journal Title: Mol Genet Metab Rep Volume: 34 Pages: 100951-100951
  • DOI: 10.1016/j.ymgmr.2022.100951
  • Peer Reviewed / Open Access
• [Journal Article] Sarcomere maturation: function acquisition, molecular mechanism, and interplay with other organelles (2022)
  • Author(s): Ahmed Razan E.、Tokuyama Takeshi、Anzai Tatsuya、Chanthra Nawin、Uosaki Hideki
  • Journal Title: Philosophical Transactions of the Royal Society B: Biological Sciences Volume: 377 Issue: 1864 Pages: 20210325-20210325
  • DOI: 10.1098/rstb.2021.0325
  • Peer Reviewed / Open Access
• [Journal Article] Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation (2022)
  • Author(s): Takeshi T, Hideki U, Ayumu S, Gen N, Keisuke T, Shun N, Isshin S, Naoki I, Taku A, Satoshi M, Akiyuki N, Motohiro N, Ayumu K, Hirokazu H, Satoshi I, Takahiro Y, Takayuki S, Shingo T, Shintaro K, Ryoko I and Shigeru Y
  • Journal Title: iScience Volume: in press
  • Peer Reviewed
• [Journal Article] MITOL promotes cell survival by degrading Parkin during mitophagy (2021)
  • Author(s): Shiiba Isshin、Takeda Keisuke、Nagashima Shun、Ito Naoki、Tokuyama Takeshi、Yamashita Shun‐Ichi、Kanki Tomotake、Komatsu Toru、Urano Yasuteru、Fujikawa Yuuta、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: EMBO reports Volume: 22 Issue: 3
  • DOI: 10.15252/embr.201949097
  • Peer Reviewed / Open Access
• [Journal Article] Disease Modeling of Mitochondrial Cardiomyopathy Using Patient-Specific Induced Pluripotent Stem Cells (2021)
  • Author(s): Tokuyama Takeshi、Ahmed Razan Elfadil、Chanthra Nawin、Anzai Tatsuya、Uosaki Hideki
  • Journal Title: Biology Volume: 10 Issue: 10 Pages: 981-981
  • DOI: 10.3390/biology10100981
  • Peer Reviewed / Open Access
• [Journal Article] MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis (2021)
  • Author(s): Kitakata Hiroki、Endo Jin、Matsushima Hirokazu、Yamamoto Shoichi、Ikura Hidehiko、Hirai Akeo、Koh Seien、Ichihara Genki、Hiraide Takahiro、Moriyama Hidenori et al.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 161 Pages: 116-129
  • DOI: 10.1016/j.yjmcc.2021.08.006
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients (2020)
  • Author(s): Tokuyama Takeshi、Hirai Asei、Shiiba Isshin、Ito Naoki、Matsuno Keigo、Takeda Keisuke、Saito Kanata、Mii Koki、Matsushita Nobuko、Fukuda Toshifumi、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: Biomolecules Volume: 10 Issue: 3 Pages: 450-450
  • DOI: 10.3390/biom10030450
  • Peer Reviewed
• [Journal Article] Critical role of CRAG, a splicing variant of centaurin-γ3/AGAP3, in ELK1-dependent SRF activation at PML bodies. (2019)
  • Author(s): Nagashima S, Takeda K, Shiiba I, Higashi M, Fukuda T, Tokuyama T, Matsushita N, Nagano S, Araki T, Kaneko M, Shioi G, Inatome R, Yanagi S.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 20107-20107
  • DOI: 10.1038/s41598-019-56559-9
  • Peer Reviewed / Open Access
• [Journal Article] MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress (2019)
  • Author(s): Nagashima Shun、Takeda Keisuke、Ohno Nobuhiko、Ishido Satoshi、Aoki Motohide、Saitoh Yurika、Takada Takumi、Tokuyama Takeshi、Sugiura Ayumu、Fukuda Toshifumi、Matsushita Nobuko、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: Life Science Alliance Volume: 2 Issue: 4 Pages: e201900308-e201900308
  • DOI: 10.26508/lsa.201900308
  • Peer Reviewed / Open Access
• [Journal Article] MITOL prevemts ER stress-induced apoptosis by IRE1 ubiquitylation at mitochondrial-ER contact sites. (2019)
  • Author(s): Takeda, K., Nagashima, S., Shiiba, I., Uda, A., Tokuyama, T., Ito, N., Fukuda, T., Matsushita, N., Ishido, S., Iwawaki, T., Uehara, T., Inatome, R., and Yanagi, S.
  • Journal Title: EMBO J. Volume: 38 Issue: 15
  • DOI: 10.15252/embj.2018100999
  • Peer Reviewed / Open Access
• [Presentation] The mitochondrial ubiquitin ligase MITOL is downregulated in myocardial infarction and induces mitophagy via mitochondrial fission. (2023)
  • Author(s): Takeshi Tokuyama
  • Organizer: 第87回日本循環器学会学術集会(JCS2023)
• [Presentation] ミトコンドリア酵素MITOLの低下は心臓老化や心筋梗塞を増悪し、 MITOLの活性化は心筋梗塞の重症化を抑制する (2022)
  • Author(s): 徳山剛士, 魚崎英毅, 柳茂
  • Organizer: 第46回日本分子生物学会年会
• [Presentation] ミトコンドリア外膜上の掃除機構の破綻が 心筋梗塞の病態を悪化させる (2022)
  • Author(s): 徳山剛士, 魚崎英毅, 柳茂
  • Organizer: 第51回日本心脈管作動物質学会
• [Presentation] Protective roles of MITOL in ischemic heart disease and heart aging partly via Drp1 regulation (2019)
  • Author(s): 徳山剛士
  • Organizer: The 16th Conference of Asian Society for Mitochondrial Research and Medicine [ASMRM] ー&ー The 19th Conference of Japanese Society of Mitochondrial Research and Medicine[J-mit]
  • Int'l Joint Research
• [Book] 実験医学増刊 Vol.41 No.5 ミトコンドリア 疾患治療の新時代 (2023)
  • Author(s): 徳山 剛士, 魚崎 英毅
  • Total Pages: 7
  • Publisher: 羊土社
  • ISBN: 9784758104098
• [Book] 小児内科 (2022)
  • Author(s): 徳山 剛士, 安済 達也, 魚崎 英毅
  • Publisher: 東京医学社
• [Book] ミトコンドリアと疾患・老化 (2019)
  • Author(s): 柳 茂
  • Total Pages: 221
  • Publisher: 羊土社
  • ISBN: 9784758103800