Fundamental Research for the Development of Novel Therapeutic Agents for Mitochondrial Diseases by Stabilizing Regulators of ATP Production

• Project/Area Number: 20K07338
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Kato Hisakazu 大阪大学, 大学院医学系研究科, 助教 (30589312)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ミトコンドリア病 / ATP / タンパク質分解 / ミトコンドリア

Outline of Research at the Start

ミトコンドリア病は、細胞内ミトコンドリアの電子伝達系障害によりATP産生が低下する疾患であるが、その根本的な治療法はない。研究代表者らは、心筋細胞において低酸素下でATP産生を増強し細胞保護的に働くATP産生制御因子G0S2のタンパク質分解メカニズムを明らかにし、分解を阻害することでATP産生を増強させる化合物、ATP合成酵素活性化剤を同定した。本研究では、ATP合成酵素活性化剤による特異的なG0S2分解阻害メカニズムの生化学的手法による解明を目指す。さらに、ATP合成酵素活性化剤の新たなミトコンドリア病治療薬としての可能性について、患者由来細胞および病態モデルマウスを用いて検討する。

Outline of Final Research Achievements

We identified a compound that enhances ATP production by inhibiting the protein degradation of the ATP production regulator G0S2. In this study, we verified the mechanism of action of this compound and its validity as a therapeutic agent for mitochondrial diseases. We found that the compound covalently binds to one amino acid within G0S2, and partly elucidated the mechanism of inhibition of its degradation. We confirmed that G0S2 is expressed in cells derived from patients of mitochondrial diseases and raised the possibility of therapeutic intervention for mitochondrial diseases. We have succeeded in developing a compound that can be administered in vivo by structural optimization, and will proceed with the therapeutic effects of this compound in patient-derived cells and administration to animal models that we already possess and are breeding.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリア病は、ミトコンドリアATP合成の低下により細胞死を引き起こし様々な臓器機能の低下を引き起こす希少疾患である。ミトコンドリア病の本質的な治療薬は未だ開発されていない。本研究で明らかにしたATP合成酵素活性化剤は、直接的に細胞内ATPを増産できる点において、画期的なミトコンドリア病の治療薬開発につながることが期待される。

Research Products

• [Journal Article] Restoration of Cardiac Myosin Light Chain Kinase Ameliorates Systolic Dysfunction by Reducing Superrelaxed Myosin (2023)
  • Author(s): Hitsumoto T, Tsukamoto O, Matsuoka K, Li J, Liu L, Kuramoto Y, Higo S, Ogawa S, Fujino N, Yoshida S, Kioka H, Kato H, Hakui H, Saito Y, Okamoto C, Inoue H, Hyejin J, Ueda K, Segawa T, Nishimura S, Asano Y, Asanuma H, Tani A, Imamura R, Komagawa S, Kanai T, Takamura M, Sakata Y, Kitakaze M, Haruta JI, Takashima S.
  • Journal Title: Circulation Volume: - Issue: 25 Pages: 1902-1918
  • DOI: 10.1161/circulationaha.122.062885
  • Peer Reviewed / Open Access
• [Journal Article] Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases. (2022)
  • Author(s): Nishida Y, Yanagisawa S, Morita R, Shigematsu H, Shinzawa-Itoh K, Yuki H, Ogasawara S, et al
  • Journal Title: Nat Commun. Volume: 13 Issue: 1 Pages: 7591-7591
  • DOI: 10.1038/s41467-022-34771-y
  • Peer Reviewed / Open Access
• [Journal Article] Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation (2022)
  • Author(s): Hakui Hideyuki、Kioka Hidetaka、Miyashita Yohei、Nishimura Shunsuke、Matsuoka Ken、Kato Hisakazu、Tsukamoto Osamu、（3人省略）、Saito Shigeyoshi、Ohta Kunio、Asanuma Hiroshi、Fu Hai Ying、Shinomiya Haruki、Yamada Noriaki、Ohtani Tomohito、Sawa Yoshiki、Kitakaze Masafumi、Takashima Seiji、Sakata Yasushi、Asano Yoshihiro
  • Journal Title: Science Translational Medicine Volume: 14 Issue: 628
  • DOI: 10.1126/scitranslmed.abf3274
  • Peer Reviewed
• [Journal Article] Gene Transfer of Skeletal Muscle-Type Myosin Light Chain Kinase via Adeno-Associated Virus 6 Improves Muscle Functions in an Amyotrophic Lateral Sclerosis Mouse Model (2022)
  • Author(s): Oya Ryohei、Tsukamoto Osamu、Hitsumoto Tatsuro、Nakahara Naoya、Okamoto Chisato、Matsuoka Ken、Kato Hisakazu、Inohara Hidenori、Takashima Seiji
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 3 Pages: 1747-1747
  • DOI: 10.3390/ijms23031747
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy (2021)
  • Author(s): Shinomiya Haruki、Kato Hisakazu、・・・・・・・・Mashimo Tomoji、・・・・・・・・・・・・・・・・Sakata Yasushi、Asano Yoshihiro
  • Journal Title: The FASEB Journal Volume: 35 Issue: 11
  • DOI: 10.1096/fj.202100800r
  • Peer Reviewed / Open Access
• [Journal Article] The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression (2021)
  • Author(s): Miyashita Y, Tsukamoto O, Matsuoka K, Kamikubo K, Kuramoto Y, Fu HY, Tsubota T, Hasuike H, Takayama T, Ito H, Hitsumoto T, Okamoto C, Kioka H, Oya R, Shinomiya H, Hakui H, Shintani Y, Kato H, Kitakaze M, Sakata Y, Asano Y, Takashima S
  • Journal Title: The FASEB Journal Volume: 35 Issue: 4
  • DOI: 10.1096/fj.202002111rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-Radioactive In Vitro Cardiac Myosin Light Chain Kinase Assays (2020)
  • Author(s): Kamikubo Kenta、Tsukamoto Osamu、Uyama-Saito Yuki、Oya Ryohei、Tsubota Tomoya、Fujino Noboru、Asano Yoshihiro、Kato Hisakazu、Matsuoka Ken、Takashima Seiji
  • Journal Title: Journal of Visualized Experiments Volume: 160 Issue: 160 Pages: 1-1
  • DOI: 10.3791/61168
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP‐170 (2020)
  • Author(s): Yashirogi Shohei、Nagao Takemasa、Nishida Yuya、Takahashi Yusuke、Qaqorh Tasneem、Yazawa Issei、Katayama Toru、Kioka Hidetaka、Matsui Tsubasa S、Saito Shigeyoshi、Masumura Yuki、Tsukamoto Osamu、Kato Hisakazu、Ueda Hiromichi、Yamaguchi Osamu、Yashiro Kenta、Yamazaki Satoru、Takashima Seiji、Shintani Yasunori
  • Journal Title: EMBO reports Volume: 22 Issue: 1
  • DOI: 10.15252/embr.202050949
  • Peer Reviewed / Open Access
• [Presentation] 新鮮臨床検体を用いた大腸癌新規標的分子の探索 (2022)
  • Author(s): 在田 麻美、加藤 久和、高橋 秀和、関戸 悠紀、波多 豪、荻野 崇之、三吉 範克、植村 守、土岐 祐一郎、江口 英利、高島 成二
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] BRAF の活性化は心筋細胞の脱分化を誘導する (2022)
  • Author(s): 上田響子、加藤久和、高島成二
  • Organizer: 第68回日本生化学会近畿支部例会
• [Presentation] BRAF V600EによるMAPKシグナルの活性化は心筋細胞の脱分化を誘導する (2022)
  • Author(s): 上田響子、加藤久和、高島成二
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] ATP合成酵素活性化剤による虚血性心疾患治療法の開発 (2022)
  • Author(s): 加藤 久和
  • Organizer: WISH＆SEEDsマッチング会 ～大学SEEDsと企業WISHをモダリティと疾病領域の2軸で結ぶ初の取組み～
  • Invited
• [Presentation] p53活性化による新規大腸癌治療法の開発 (2021)
  • Author(s): 徳山 信嗣,高橋 秀和, 加藤 久和, 藤野 志季, 荻野 崇之, 三吉 範克, 植村 守, 山本 浩文, 水島 恒和, 高島 成二, 土岐 祐一郎, 江口 英利
  • Organizer: 第121回日本外科学会定期学術集会
• [Remarks] 大阪大学大学院医学系研究科医化学講座
  • URL: http://medbio.sakura.ne.jp/