TFEB dependent and independent 'post-lysosomal signals' regulating somatic and reproductive lifespan

• Project Area: Post-lysosome: Understanding of Higher-order Biological Processes initiated by the site of degradation
• Project/Area Number: 21H05145
• Research Category: Grant-in-Aid for Transformative Research Areas (B)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• Research Institution: Nara Medical University (2023); Osaka University (2021-2022)
• Principal Investigator: Nakamura Shuhei 奈良県立医科大学, 医学部, 教授 (00510611)
• Project Period (FY): 2021-08-23 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥35,490,000 (Direct Cost: ¥27,300,000、Indirect Cost: ¥8,190,000); Fiscal Year 2023: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000); Fiscal Year 2022: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000); Fiscal Year 2021: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: リソソーム / TFEB / 線虫 / オートファジー / 老化 / 寿命 / ポストリソソーム / HLH-30 / 生殖 / 生殖寿命

Outline of Research at the Start

我々の体は、精子や卵になる生殖細胞系列とそれ以外の体細胞とで構成されるが、生殖細胞系列の寿命(生殖寿命)と体細胞の寿命(個体寿命)がどのように制御され、互いに連携しているのかよく分かっていない。本研究ではリソソーム生合成のマスター転写因子として知られるTFEBによるリソソーム機能亢進とこれに伴う「ポストリソソームシグナル」の変化がこれらの制御、連携に必須の役割を果たしていると考え、このメカニズムを明らかにする。また生殖寿命の制御に関してTFEBに依存しないメカニズムの存在も示唆されており、この詳細を明らかにする。領域内共同研究を通して種を超えた個体・生殖寿命制御・連携メカニズム解明を目指す。

Outline of Final Research Achievements

We found that the neuronal function of MML-1, a transcription factor that regulates autophagy and lysosomal function independently of TFEB, is essential for activation of autophagy in other tissues, which is important for life span extension associated with germ cell removal (Shioda et al., PNAS, 2023). We also identified HKDC1, a member of the hexokinase family, as a new factor downstream of TFEB, which is essential for the maintenance of mitochondria and lysosomes through the formation of contact sites of both organelle and is required to prevent cellular senescence (Cui et al., PNAS, 2024).

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に直面する先進諸国において健康寿命の延伸は喫緊の課題であり、ヒトにおいて老化の抑制を真に実現するには老化・寿命制御の確固たる分子メカニズムの理解が不可欠である。本研究で行ったTFEBおよびMML-1を中心とした解析から、寿命や老化制御の理解とポストリソソームシグナルの実体解明に大きく貢献することができた。得られた知見をもとにさらに研究を進めることで健康寿命延伸にむけた分子メカニズム解明に寄与できると確信する。

Research Products

• [Journal Article] HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence (2024)
  • Author(s): 1.Cui, M., Yamano, K., Yamamoto, K., Yamamoto-Imoto, H., Minami, S., Yamamoto, T., Matsui, S., Kaminishi, T., Shima, T., Ogura, M., Tsuchiya, M., Nishino, K., Layden B., Kato, H., Ogawa, H., Oki, S., Okada, Y., Isaka, Y., Kosako, H., Matsuda, N., *Yoshimori, T., *Nakamura, S.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 121 Issue: 2
  • DOI: 10.1073/pnas.2306454120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysophagy protects against propagation of α-synuclein aggregation through ruptured lysosomal vesicles (2023)
  • Author(s): Kakuda Keita、Ikenaka Kensuke、Kuma Akiko、Doi Junko、Aguirre Cesar、Wang Nan、Ajiki Takahiro、Choong Chi-Jing、Kimura Yasuyoshi、Badawy Shaymaa Mohamed Mohamed、Shima Takayuki、Nakamura Shuhei、Baba Kousuke、Nagano Seiichi、Nagai Yoshitaka、Yoshimori Tamotsu、Mochizuki Hideki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 121 Issue: 1
  • DOI: 10.1073/pnas.2312306120
  • Peer Reviewed / Open Access
• [Journal Article] Microautophagy regulated by <scp>STK38</scp> and <scp>GABARAPs</scp> is essential to repair lysosomes and prevent aging (2023)
  • Author(s): Ogura Monami、Kaminishi Tatsuya、Shima Takayuki、Torigata Miku、Bekku Nao、Tabata Keisuke、Minami Satoshi、Nishino Kohei、Nezu Akiko、Hamasaki Maho、Kosako Hidetaka、Yoshimori Tamotsu、Nakamura Shuhei
  • Journal Title: EMBO reports Volume: 24 Issue: 12
  • DOI: 10.15252/embr.202357300
  • Peer Reviewed / Open Access
• [Journal Article] The TMEM192-mKeima probe specifically assays lysophagy and reveals its initial steps (2023)
  • Author(s): Shima Takayuki、Ogura Monami、Matsuda Ruriko、Nakamura Shuhei、Jin Natsuko、Yoshimori Tamotsu、Kuma Akiko
  • Journal Title: Journal of Cell Biology Volume: 222 Issue: 12
  • DOI: 10.1083/jcb.202204048
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell nonautonomous autophagic and peroxidase activity (2023)
  • Author(s): Shioda Tatsuya、Takahashi Ittetsu、Ikenaka Kensuke、Fujita Naonobu、Kanki Tomotake、Oka Toshihiko、Mochizuki Hideki、Antebi Adam、Yoshimori Tamotsu、Nakamura Shuhei
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 39
  • DOI: 10.1073/pnas.2221553120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] リソソーム損傷応答とその生理学的意義 (2023)
  • Author(s): 小倉もな美，吉森 保，中村修平
  • Volume: 41
  • Pages: 1733
  • DOI: 10.18958/7277-00001-0000509-00
• [Journal Article] 【抗老化医療の未来をさぐる:哺乳類における老化・寿命制御の理解とその社会実装】オートファジーと老化 (2023)
  • Author(s): 中村 修平, 井本 ひとみ, 吉森 保
  • Journal Title: Geriatric Medicine Volume: 61(1) Pages: 45-49
• [Journal Article] PACSIN1 is indispensable for amphisome-lysosome fusion during basal autophagy and subsets of selective autophagy (2022)
  • Author(s): Oe Yukako、Kakuda Keita、Yoshimura Shin-ichiro、Hara Naohiro、Hasegawa Junya、Terawaki Seigo、Kimura Yasuyoshi、Ikenaka Kensuke、Suetsugu Shiro、Mochizuki Hideki、Yoshimori Tamotsu、Nakamura Shuhei
  • Journal Title: PLOS Genetics Volume: 18 Issue: 6 Pages: e1010264-e1010264
  • DOI: 10.1371/journal.pgen.1010264
  • Peer Reviewed / Open Access
• [Journal Article] Measurement of autophagy via LC3 western blotting following DNA-damage-induced senescence (2022)
  • Author(s): Yamamoto-Imoto Hitomi、Hara Eiji、Nakamura Shuhei、Yoshimori Tamotsu
  • Journal Title: STAR Protocols Volume: 3 Issue: 3 Pages: 101539-101539
  • DOI: 10.1016/j.xpro.2022.101539
  • Peer Reviewed / Open Access
• [Journal Article] Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response (2022)
  • Author(s): Yamamuro Tadashi、Nakamura Shuhei、Yanagawa Kyosuke、Tokumura Ayaka、Kawabata Tsuyoshi、Fukuhara Atsunori、Teranishi Hirofumi、Hamasaki Maho、Shimomura Iichiro、Yoshimori Tamotsu
  • Journal Title: Autophagy Volume: - Issue: 11 Pages: 1-11
  • DOI: 10.1080/15548627.2022.2047341
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protocols to monitor TFEB activation following lysosomal damage in cultured cells using microscopy and immunoblotting (2022)
  • Author(s): Ogura Monami、Shima Takayuki、Yoshimori Tamotsu、Nakamura Shuhei
  • Journal Title: STAR Protocols Volume: 3 Issue: 1 Pages: 101018-101018
  • DOI: 10.1016/j.xpro.2021.101018
  • Peer Reviewed / Open Access
• [Journal Article] Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis (2022)
  • Author(s): Yamamoto-Imoto Hitomi et al.,
  • Journal Title: Cell Reports Volume: 38 Issue: 9 Pages: 110444-110444
  • DOI: 10.1016/j.celrep.2022.110444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy system as a potential therapeutic target for neurodegenerative diseases (2022)
  • Author(s): Cui Mengying、Yoshimori Tamotsu、Nakamura Shuhei
  • Journal Title: Neurochemistry International Volume: 155 Pages: 105308-105308
  • DOI: 10.1016/j.neuint.2022.105308
  • Peer Reviewed
• [Journal Article] Non-canonical roles of ATG8 for TFEB activation (2022)
  • Author(s): Nakamura Shuhei、Akayama Shiori、Yoshimori Tamotsu
  • Journal Title: Biochemical Society Transactions Volume: 50 Issue: 1 Pages: 47-54
  • DOI: 10.1042/bst20210813
  • Peer Reviewed
• [Journal Article] Rubicon in Metabolic Diseases and Ageing (2022)
  • Author(s): Minami Satoshi、Nakamura Shuhei、Yoshimori Tamotsu
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9 Pages: 816829-816829
  • DOI: 10.3389/fcell.2021.816829
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic potential of Beclin1 for transition from AKI to CKD: autophagy-dependent and autophagy-independent functions (2022)
  • Author(s): Minami Satoshi、Nakamura Shuhei
  • Journal Title: Kidney International Volume: 101 Issue: 1 Pages: 13-15
  • DOI: 10.1016/j.kint.2021.10.021
  • Peer Reviewed / Open Access
• [Presentation] オートファジー・リソソーム分解系による老化抑制機構の解明 (2023)
  • Author(s): 中村修平
  • Organizer: 第13回腎不全研究会
  • Invited
• [Presentation] オートファジーによる寿命・老化制御メカニズム (2023)
  • Author(s): 中村修平
  • Organizer: 第３回日本オートファジーコンソーシアムシンポジウム
  • Invited
• [Presentation] リソソーム恒常性維持の分子機構と細胞老化における役割 (2023)
  • Author(s): 中村修平
  • Organizer: 第96回日本生化学会大会
  • Invited
• [Presentation] Molecular Mechanisms Maintaining Lysosomal Homeostasis and Its Roles in Aging (2023)
  • Author(s): Shuhei Nakamura
  • Organizer: Asian-Pacific Society for Neurochemistry (APSN) Webinar Series
  • Int'l Joint Research / Invited
• [Presentation] オートファジー・リソソーム分解系の制御機構と老化・寿命制御における役割 (2023)
  • Author(s): 中村修平
  • Organizer: 第22回日本メンズヘルス医学会シンポジウム
  • Invited
• [Presentation] リソソーム損傷応答の分子機構とその生理学的意義 (2022)
  • Author(s): 中村修平
  • Organizer: 第95回日本生化学会大会
  • Invited
• [Book] 実験医学2023年7月号 (2023)
  • Author(s): 中村 修平
  • Total Pages: 133
  • Publisher: 羊土社
  • ISBN: 9784758125697
• [Book] Aging Mechanism II: Longevity, Metabolism and Brain Aging (2022)
  • Author(s): *Nakamura, S., Shioda, T., *Yoshimori, T
  • Publisher: Springer
• [Remarks] オートファジー分解経路を制御する新たな因子を発見
  • URL: https://www.fbs.osaka-u.ac.jp/ja/research_results/papers/detail/1045