AMPK impairment caused by gelatin disturbs mitochondrial dynamics leading to enhanced phagocytosis of bacteria in PMA-stimulated U937 cells

  • Cell Signal. 2025 Nov:135:111985. doi: 10.1016/j.cellsig.2025.111985.
Kaihui Chen  1 ,  Xiaoli Sun  1 ,  Yue Feng  1 ,  Shunuo Jiang  1 ,  Toshihiko Hayashi  2 ,  Kikuji Itoh  3 ,  Kazunori Mizuno  4 ,  Shunji Hattori  4 ,  Hitomi Fujisaki  4 ,  Weiwei Liu  5 ,  Takashi Ikejima  6
Affiliations
  • 1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.
  • 2. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan.
  • 3. Biochemical Center, Japan SLC Inc., Shizuoka 431-1103, Japan.
  • 4. Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan.
  • 5. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China. Electronic address: [email protected].
  • 6. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China. Electronic address: [email protected].
PMID: 40653043 DOI: 10.1016/j.cellsig.2025.111985
Abstract

In scenarios like burns or local infections, monocytes migrate from the circulatory system to the injured sites, which are rich in extracellular matrix (ECM) components, Collagen and its derivative gelatin, to differentiate into macrophages. The roles of ECM components in the phagocytosis of macrophages raised our interest. We previously found that precoating the culture dishes with gelatin markedly enhances phagocytosis of bacteria in PMA-stimulated human lymphoma U937 cells which have macrophage-like properties. But type I Collagen has no such effects. Here we reveal that AMPK pathway is impaired in gelatin-treated U937 cells, and this subsequently induces mitochondrial fission. Mitochondrial fission further leads to mitochondrial dysfunction and leakage of mitochondrial DNA into the cytoplasm, activating the STING pathway which is responsible for the enhanced phagocytosis. Additionally, mitochondrial dysfunction impairs aerobic respiration and this compensatively elevates glycolytic levels, contributing to the enhanced phagocytosis. In summary, our study comprehensively unveils that gelatin promotes bacteria phagocytosis via modulating an AMPK-mitochondrial fission axis, which leads to the STING activation and glycolytic reprogramming. Our findings offer new insights for the influence of gelatin on immune cells.

Keywords
AMPK; Gelatin; Glycolysis; Macrophages; Mitochondrial dynamics; Phagocytosis.
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