2024年1月9日 / 最終更新日 : 2024年1月16日 ad_y ニュース

2024年 新着論文 1　細胞情報学分野から論文が発表されました

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

Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2306454120. doi: 10.1073/pnas.2306454120. Epub 2024 Jan 3.

Authors

Mengying Cui  1 , Koji Yamano  2   3 , Kenichi Yamamoto  4   5 , Hitomi Yamamoto-Imoto  1 , Satoshi Minami  1   6 , Takeshi Yamamoto  6 , Sho Matsui  6 , Tatsuya Kaminishi  1   7 , Takayuki Shima  8 , Monami Ogura  9 , Megumi Tsuchiya  10 , Kohei Nishino  11 , Brian T Layden  12   13 , Hisakazu Kato  14 , Hidesato Ogawa  10 , Shinya Oki  15 , Yukinori Okada  4   7   16 , Yoshitaka Isaka  6 , Hidetaka Kosako  11 , Noriyuki Matsuda  2   3 , Tamotsu Yoshimori  1   7   9 , Shuhei Nakamura  8

Affiliations

  • 1 Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • 2 Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
  • 3 Department of Biomolecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
  • 4 Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • 5 Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • 6 Department of Nephrology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • 7 Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan.
  • 8 Department of Biochemistry, Nara Medical University, Kashihara, Nara 634-8521, Japan.
  • 9 Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
  • 10 Laboratory of Nuclear Dynamics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
  • 11 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
  • 12 Division of Endocrinology, Diabetes, and Metabolism, University of Illinois Chicago, Chicago, IL 60612.
  • 13 Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612.
  • 14 Department of Medical Biochemistry, Graduate School of Medicine/Frontier Bioscience, Osaka University, Suita, Osaka 565-0871, Japan.
  • 15 Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • 16 Laboratory of Statistical Immunology, Immunology Frontier Research Center, World Premier International Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan.

Abstract

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.

Keywords: HKDC1; TFEB; cellular senescence; mitochondria–lysosome contact; mitophagy.

Conflict of interest statement

Competing interests statement:T. Yoshimori and S.N. are founders of AutoPhagyGO.

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