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Abstract: SA-PO1008

ULK1-Regulated AMP Sensing Mechanism by AMPK Is Disrupted in CKD

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Yanagi, Tomoki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Kikuchi, Hiroaki, National Heart Lung and Blood Institute, Bethesda, Maryland, United States
  • Takeuchi, Koh, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Susa, Koichiro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Takahashi, Naohiro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Nakano, Yuta, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Ando, Fumiaki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Mandai, Shintaro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Mori, Takayasu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Honda, Shinya, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Torii, Satoru, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Shimizu, Shigeomi, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Sohara, Eisei, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan
Background

AMP-activated protein kinase (AMPK) is a kinase that plays a major role in energy homeostasis. Increase in intracellular AMP causes AMPK activation through binding of AMP to AMPK γ-subunit, however, this phenomenon is impaired in chronic kidney disease (CKD). To date, the molecular mechanism of regulation of AMP sensing ability of AMPK, and the mechanism by which this AMP sensitivity is disrupted in CKD are totally unclear. We show a possible role for Unc-51-like kinase 1 (ULK1), whose expression is markedly decreased in CKD, in the regulation of this AMP sensing of AMPK.

Methods

Ulk1-/- mice were used in this study. Sub-total nephrectomy was applied as CKD mouse model. Purified AMPKγ protein and fluorescently labeled AMP were used to measure the amount of AMP that binds to the AMPKγ subunit.

Results

The activation of AMPK by AMP was impaired in Ulk1-/- mice, in spite of increased AMP/ATP ratio. We identify that ULK1 directly phosphorylates AMPKγ1, which is required for the activation AMPK, and that this phosphorylation is decreased in Ulk1-/- and CKD mouse kidney. Fluorescence binding assay reveals that the amount of AMP bound to AMPKγ1 is regulated by phosphorylation of AMPKγ1. Structural information also indicated that this phosphorylation could affect the AMP binding loops' conformation, modifying the AMP binding affinity to AMPKγ1. Absence of ULK1 promote more severe kidney dysfunction and renal fibrosis, due to AMPK inactivation.

Conclusion

We discovered an entirely new mechanism of energy homeostasis, in which ULK1 increases AMPK activity promoting AMP binding to AMPK γ1 subunit, providing potential insight into the role of this new mechanism for AMP sensing failure of AMPK in CKD.