Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Meyers, Allison K.; Wang, Zhan; Han, Wenzheng; Zhao, Qi; Zabalawi, Manal; Duan, Likun; Liu, Juan; Manne, Rajesh Kumar; Lorenzo, Felipe; Quinn, Matthew; Song, Qisheng; Fan, Daping; Lin, Hui-Kuan; Furdui, Cristina M.; Locasale, Jason W.; McCall, Charles E.; Zhu, Xuewei

doi:10.1016/j.celrep.2022.111941

Cited by 7 publications

(1 citation statement)

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“…S1) [4]. While regulatory phosphorylation of PDC has been well established in sepsis, even leading to a promising new therapeutic approach [13][14][15][16][17], much remains to be learned about redox regulation of PDC.…”

Section: Introductionmentioning

confidence: 99%

Glutathionylation of Pyruvate Dehydrogenase Complex E2 and Inflammatory Cytokine Production During Acute Inflammation Are Magnified By Mitochondrial Oxidative Stress

Long

Poole

McCall

2023

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Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9.5 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, both LPS and MitoCDNB together are synergistic for PDCE2 glutathionylation, ROS production, and cell death. These results suggest that glutathionylation on PDCE2 lipoamide sulfurs is a specific modification associated with LPS and cell death which is not recapitulated by a general rise in mitochondrial ROS, but is enhanced after LPS treatment by rising oxidative stress exerted by MitoCDNB that impairs reductase systems.

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