Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival

Abstract

Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists' ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.

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

“…THP‐1 cells were maintained in RPMI‐1640 media supplemented with 10% FBS (Gemini Bioproducts, West Sacramento, CA, USA), 2 mM glutamine, and penicillin/streptomycin at a density of between 0.3 × 10 6 and 1 × 10 6 cells per ml; and media replenished every 2–3 d. On the day of the experiments, THP‐1 cells were stimulated with a high dose (1 µg/ml) of LPS ( E. Coli 0111; B4, Sigma‐Aldrich, St. Louis, MO, USA) for 0–24 h, as indicated in the figure legends, in culture media and 5 mM DCA (Sigma‐Aldrich) was added to the cells 30 min before LPS activation; medium was the vehicle control. As previously reported, DCA decreased PDC phosphorylation within 30–60 min (data not shown).…”

“…We found that PDC activation and pyruvate decarboxylation induced by DCA increased the levels of TCA cycle intermediates that usually control anabolism, decreased the level of itaconate that supports tolerance, and enhanced catabolism‐dependent anaplerotic functions of BCAAs. Our findings support the concept that PDC is a crucial mitochondrial energy homeostat and that PDK is a druggable target for treating clinical inflammatory shock syndromes …”

“…Increased expression of one or more PDK isoforms occurs consistently in acute or chronic inflammatory conditions, inhibiting the activity of PDC, disrupting OXPHOS, and accelerating glycolysis and lactate production (Warburg metabolism). A life‐threatening example of this metabolic perturbation is septic shock, in which decreased synthesis of acetyl‐CoA limits TCA cycle‐supported anabolism and converts the high energy demands required to resist the inflammatory threat to a tolerable, catabolic low‐energy supply state . The loss of anabolic biosynthetic pathways develops within hours of the onset of “inflammatory shock” and directs the state of tolerance by diverting the TCA cycle intermediate cis ‐aconitate to itaconate.…”

“…18 PDK and PDP isoforms have variable tissue expression 19,20 and are modulated, in turn, by numerous endogenous molecules and xenobiotics. 21,22 Increased expression of one or more PDK isoforms occurs consistently in acute [23][24][25][26] or chronic [27][28][29][30] inflammatory conditions, inhibiting the activity of PDC, disrupting OXPHOS, and accelerating glycolysis and lactate production (Warburg metabolism). A life-threatening example of this metabolic perturbation is septic shock, in which decreased synthesis of acetyl-CoA limits TCA cycle-supported anabolism and converts the high energy demands required to resist the inflammatory threat to a tolerable, catabolic low-energy supply state.…”

“…A life-threatening example of this metabolic perturbation is septic shock, in which decreased synthesis of acetyl-CoA limits TCA cycle-supported anabolism and converts the high energy demands required to resist the inflammatory threat to a tolerable, catabolic low-energy supply state. 27 The loss of anabolic biosynthetic pathways develops within hours of the onset of "inflammatory shock" and directs the state of tolerance by diverting the TCA cycle intermediate cis-aconitate to itaconate.…”