HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence

• 成果类型: Article
• 署名作者: Cui, Mengying; Yamano, Koji; Yamamoto, Kenichi; Yamamoto-Imoto, Hitomi; Minami, Satoshi; Yamamoto, Takeshi; Matsui, Sho; Kaminishi, Tatsuya; Shima, Takayuki; Ogura, Monami; Tsuchiya, Megumi; Nishino, Kohei; Layden, Brian T.; Kato, Hisakazu; Ogawa, Hidesato; Oki, Shinya; Okada, Yukinori; Isaka, Yoshitaka; Kosako, Hidetaka; Matsuda, Noriyuki; Yoshimori, Tamotsu; Nakamura, Shuhei
• 署名单位: University of Osaka; Tokyo Metropolitan Institute of Medical Science; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); University of Osaka; University of Osaka; University of Osaka; University of Osaka; Nara Medical University; University of Osaka; University of Osaka; Tokushima University; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; US Department of Veterans Affairs; Veterans Health Administration (VHA); Jesse Brown VA Medical Center; University of Osaka; Kyoto University; University of Osaka
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11668
• DOI: 10.1073/pnas.2306454120
• 发表日期: 2024-01-09
• 关键词: autophagy; identification; biogenesis; mitophagy; import; parkin; pink1; gene

摘要

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.