Sepsis, pyruvate, and mitochondria energy supply chain shortage

Abstract

Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.

Keywords: dichloroacetate; energy shifts; evolution; immunometabolism; inflammation; itaconate; pyruvate; redox.

FIGURE 1

Sepsis energy trade‐off. As a universal principle of survival, acute stress responses balance energy demands necessary to resist physical illness and injury with energy conservation to tolerate and survive. Molecular events associated with resistance and tolerance overlap, but 1 of the 2 usually dominates and both are life threatening. The severe stress of sepsis often leads to an energy imbalance, immunometabolic “paralysis” and energy depletion that is unresolved. Many sepsis patients experience a mechanistically obscure and persistent low‐grade inflammation, unrelenting immune suppression, and chronic disability with continued increases in mortality. Our studies in animal sepsis models, ex vivo analyses of cells from septic animals, and in vitro human cell sepsis models suggest that pyruvate is poised at the intersection of pathways that provide key energy metabolites including carbohydrates, fatty acids, and acetyl CoA. Further understanding pyruvate metabolism may enlighten therapeutic options for improving sepsis outcomes.

FIGURE 2

Regulation of PDC activity. Rapid posttranslational regulation of PDC is affected by its reversible phosphorylation by tissue selective actions of PDC kinases (PDK) and phosphatases (PDP). DCA inhibits PDK and activates PDC. During aerobic respiration, pyruvate is decarboxylated by PDC and produces acetyl‐CoA

FIGURE 3

DCA increases survival in a mouse model of sepsis. To assess the effect of DCA on survival, we used a mouse model of sepsis (CLP) as previously described. At 24 h after CLP, mice were treated with a single intraperitoneal dose of 25 mg/kg of DCA (CLP+DCA) or a vehicle control (CLP + vehicle). Kaplan–Maier survival curve shows that DCA (CLP + DCA) significantly improved 14‐day survival when compared with vehicle treatment (CLP + vehicle) in the absence of antibiotics. N = 20 mice/cohort; Log‐rank (Mantel–Cox) test, **p < 0.01

FIGURE 4

PDC activation broadly alters intermediary metabolism in a cell culture model of sepsis. Using endotoxin (E. coli 0111:B4) treatment (1 μg/ml)' , THP‐1 cell‐line monocytes were pretreated with vehicle (untreated) or with DCA for 30 min and subsequently stimulated without or with LPS for the indicated time(s). For each time point, fold change differences of intracellular metabolites of LPS relative to untreated cells (LPS) and DCA + LPS relative to LPS stimulated cells (DCA + LPS) are shown. Green (decrease) boxes indicate significant difference (p ≤ 0.05) between the groups shown; metabolite ratio of <1.00. Light green boxes indicate narrowly missed statistical cutoff for significance 0.05 < p < 0.10; metabolite ratio of <1.00. Red (increase) boxes indicate significant difference (p ≤ 0.05) between the groups shown; metabolite ratio of ≥1.00. Pink boxes indicate narrowly missed statistical cutoff for significance 0.05 < p < 0.10; metabolite ratio of ≥1.00. N = 5