TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes

• DOI: 10.1073/pnas.2218150120
• Publication Date: 2023-09-11T19:07:41Z
• Authors: Nabil E. Boutagy; Joseph W. Fowler; Kariona A. Grabinska; Rebecca Cardone; Qiushi Sun; Kyla R. Vazquez; Michael B. Whalen; Xiaolong Zhu; Raja Chakraborty; Kathleen A. Martin; Michael Simons; Casey E. Romanoski; Richard G. Kibbey; William C. Sessa
• Keywords: Proinflammatory cytokine

The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure endothelial cells (EC) to stimuli leads an increase in mitochondrial metabolism; however, function and regulation elevated metabolism EC response cytokines remain unclear. Studies using high-resolution metabolomics 13 C-glucose C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) oxidative tricarboxylic acid cycle (TCA) are human umbilical vein ECs overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated mediated these metabolic changes via mitochondrial-specific protein degradation kinase 4 (PDK4, inhibitor PDH) by Lon protease NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown catalytically active subunit PDH, PDHE1α ( PDHA1 gene), we show PDH controls transcription approximately one-third genes up-regulated stimulation. Notably, TNFα-induced regulates unique signature mediators (cytokines chemokines) but not inducible adhesion molecules. Metabolomics ChIP for acetylated modification on lysine 27 histone 3 (H3K27ac) promotes acetylation specific gene loci citrate accumulation ATP-citrate lyase–mediated generation acetyl CoA. Together, results uncover mechanism which signaling increases TCA glucose support through extramitochondrial CoA acetylation.