2. Academic Validation
  3. Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked

Potassium ion efflux induces exaggerated mitochondrial damage and non-pyroptotic necrosis when energy metabolism is blocked

  • Free Radic Biol Med. 2023 Dec 25:212:117-132. doi: 10.1016/j.freeradbiomed.2023.12.029.
Rong Xu 1,  Li-Sha Yuan 2,  Ying-Qing Gan 2,  Na Lu 2,  Ya-Ping Li 3,  Zhi-Ya Zhou 2,  Qing-Bing Zha 4,  Xian-Hui He 5,  Tak-Sui Wong 6,  Dong-Yun Ouyang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 2 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 3 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China.
  • 4 Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China; Department of Fetal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 5 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Department of Clinical Laboratory, The Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China. Electronic address: thexh@jnu.edu.cn.
  • 6 Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: huangdx@jnu.edu.cn.
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: dongyun1967@aliyun.com.
PMID: 38151213 DOI: 10.1016/j.freeradbiomed.2023.12.029
Abstract

Damage-associated molecular patterns (DAMPs) such as extracellular ATP and nigericin (a Bacterial toxin) not only act as potassium ion (K+) efflux inducers to activate NLRP3 inflammasome, leading to Pyroptosis, but also induce cell death independently of NLRP3 expression. However, the roles of energy metabolism in determining NLRP3-dependent Pyroptosis and -independent necrosis upon K+ efflux are incompletely understood. Here we established cellular models by pharmacological blockade of energy metabolism, followed by stimulation with a K+ efflux inducer (ATP or nigericin). Two energy metabolic inhibitors, namely CPI-613 that targets α-ketoglutarate dehydrogenase and pyruvate dehydrogenase (a rate-limiting Enzyme) and 2-deoxy-d-glucose (2-DG) that targets Hexokinase, are recruited in this study, and NLRP3 gene knockout macrophages were used. Our data showed that CPI-613 and 2-DG dose-dependently inhibited NLRP3 inflammasome activation, but profoundly increased cell death in the presence of ATP or nigericin. The cell death was K+ efflux-induced but NLRP3-independent, which was associated with abrupt Reactive Oxygen Species (ROS) production, reduction of mitochondrial membrane potential, and oligomerization of mitochondrial proteins, all indicating mitochondrial damage. Notably, the cell death induced by K+ efflux and blockade of energy metabolism was distinct from Pyroptosis, Apoptosis, Necroptosis or Ferroptosis. Furthermore, fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, significantly suppressed CPI-613+nigericin-induced mitochondrial damage and cell death. Collectively, our data show that energy deficiency diverts NLRP3 inflammasome activation-dependent Pyroptosis to Nlrp3-independent necrosis upon K+ efflux inducers, which can be dampened by high-energy intermediate, highlighting a critical role of energy metabolism in cell survival and death under inflammatory conditions.

Keywords

Fructose-1,6-bisphosphate; Glucose metabolism; Mitochondrial damage; NLRP3 inflammasome activation; Potassium efflux; Reactive oxygen species.

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