Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Abstract

The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate‐derived cis‐aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA‐induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched‐chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA‐stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

“…Our similar findings within the liver during the prolonged phase of sepsis suggests this organ may utilize similar mechanisms to promote tissue tolerance during chronic sepsis. Intriguingly, DCA reduces itaconate levels, which we also find in a human monocyte model of sepsis ( Zhu et al, 2020 ).…”

“…PDC is a master metabolic regulator controlling the conversion of pyruvate to acetyl-CoA in the mitochondria ( Stacpoole, 2012 ) and its inactivation contributes to the metabolic reprogramming that occurs in immune cells in response to inflammatory signaling ( Zhu et al, 2020 ; Stacpoole, 2012 ). PDK is a negative regulator of the PDC, as it phosphorylates PDC and inhibits the conversion of pyruvate to acetyl-CoA ( Stacpoole, 2012 ).…”

“…We reported in a sepsis monocyte model that DCA reduced TCA cycle catabolic effects concurrent with increasing amino acid anaplerotic catabolism of branched-chain amino acids, leading to increased TCA-driven anabolic energetics ( Zhu et al, 2020 ). In the present study, we find restoration of hepatic TCA metabolites, decreased triglyceride accumulation, lessening of lipid synthesis, and ammelioration of oxidative stress in septic mice after DCA administration.…”

“…This enzyme is one of four PDK isoforms that reversibly phosphorylates serine residues on pyruvate dehydrogenase complex (PDC) E1a subunit, inhibiting the conversion of pyruvate to acetyl coenzyme A (acetyl-CoA) ( Stacpoole, 1989 ). Inhibition of this important enzyme central to glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and the lipogenic pathway is thought to be an important mechanism driving the dysfunction of mitochondrial respiration and cell bioenergetics observed during sepsis ( McCall et al, 2018 ; Zhu et al, 2020 ). Therefore, PDK serves as a potential therapeutic target as its inhibition would allow for the downstream oxidation of glucose to continue, restoring OXPHOS and mitochondrial function known to be altered in both immune and non-immune cells during sepsis ( Seymour et al, 2013 ; McCall et al, 2018 ; Kelly and O'Neill, 2015 ; Eyenga et al, 2018 ).…”

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

“…This enzyme is one of four PDK isoforms that reversibly phosphorylates serine residues on pyruvate dehydrogenase complex (PDC) E1a subunit, inhibiting the conversion of pyruvate to acetyl coenzyme A (acetyl CoA) 21 . Inhibition of this important enzymatic activity that connects glycolysis to tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and the lipogenic pathway is thought to be an important mechanism driving the dysfunction of mitochondrial respiration and cell bioenergetics observed during sepsis 19,22 . Therefore, PDK serves as a potential therapeutic target as it can allow for the downstream oxidation of glucose to continue, restoring OXPHOS and mitochondrial functioning that we know to be altered in both immune and non-immune cells during sepsis 16,19,23,24 .…”