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Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Year: 2023
Type: article
Abstract: Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we showed that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuated macrophage NLRP3 inflammasome activation. Broad rewiring of intracellular metabolism and enhanced autophagic flux occurred in inflammasome-activated macrophages, but neither was necessary for the PDHK-regulated reduction of NLRP3 inflammasome activity. PDHK inhibition protected against inflammation-induced mitochondrial fragmentation and cristae remodeling and improved mitochondrial function by repurposing mitochondria from ROS production to ATP generation. Inhibition of PDHK increased the expression of the mitochondrial fusion protein optic atrophy-1 (OPA1). Suppression of OPA1 partially reversed the effect of PDHK inhibition on NLRP3 inflammasome activation. In conclusion, our study suggests that inhibition of PDHK dampens macrophage NLRP3 inflammasome activation during acute inflammation by ameliorating mitochondrial damage in a mechanism separate from its canonical role as a metabolic regulator.
Source: Cell Reports
DOI: 10.1016/j.celrep.2022.111941
Authors: Allison K. Meyers, Zhan Wang, Wenzheng Han, Qingxia Zhao, Manal Zabalawi, Likun Duan, Juan Liu, Qianyi Zhang, Rajesh K. Manne, Felipe Lorenzo, Matthew A. Quinn, Qianqian Song, Daping Fan, Hui-Kuan Lin, Cristina M. Furdui, Jason W. Locasale, Charles E. McCall, Xuewei Zhu
Institutions: Wake Forest University Health Sciences, Wake Forest University, Fudan University, Huadong Hospital, Duke University, Duke Medical Center, University of South Carolina
Language: English
Open Access status: gold
Estimated APC paid: $5,460
Funders: Wake Forest University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences
Awards: The role of SLC37A2, a glucose 6 phosphate transporter, in inflammation and metabolic diseases, G3291197270, G3549828030, G3952696733, G4470702900, G4823677270, G5520316217, G6642529182, G6980329202, G8147851227, G9000014006, G9000038858, G9000040490, G9000099230, G9000160004, G9000231286, G9000262265, G94668252
OpenAlex ID: W4313854937
FWCI: 4.17
Cites: 105
Cited by: 55
Related to: 10