※ をクリックすると外部の論文のサイトが開きます。
論文
- タイトル
- タイトル（英）
- HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
- 参照URL
- https://researchmap.jp/N-Matsuda/published_papers/44395229
- 著者
- 著者（英）
- Mengying Cui,Koji Yamano,Kenichi Yamamoto,Hitomi Yamamoto-Imoto,Satoshi Minami,Takeshi Yamamoto,Sho Matsui,Tatsuya Kaminishi,Takayuki Shima,Monami Ogura,Megumi Tsuchiya,Kohei Nishino,Brian T Layden,Hisakazu Kato,Hidesato Ogawa,Shinya Oki,Yukinori Okada,Yoshitaka Isaka,Hidetaka Kosako,Noriyuki Matsuda,Tamotsu Yoshimori,Shuhei Nakamura
- 担当区分
- 概要
- 概要（英）
- Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Proceedings of the National Academy of Sciences of the United States of America
- 巻
- 121
- 号
- 2
- 開始ページ
- e2306454120
- 終了ページ
- 出版年月
- 2024年1月9日
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1073/pnas.2306454120
- 共同研究・競争的資金等の研究課題