Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis

PLoS One. 2020 Nov 5;15(11):e0241122. doi: 10.1371/journal.pone.0241122. eCollection 2020.

Abstract

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Animals
  • Citric Acid Cycle / drug effects
  • Dichloroacetic Acid / pharmacology*
  • Drosophila melanogaster / drug effects*
  • Drosophila melanogaster / metabolism*
  • Glycolysis / drug effects
  • Inflammation / metabolism
  • Lactic Acid / metabolism
  • Longevity / drug effects*
  • Oxidative Phosphorylation / drug effects
  • Pyruvate Dehydrogenase Complex / metabolism
  • Pyruvic Acid / metabolism
  • Sepsis / drug therapy*
  • Sepsis / metabolism

Substances

  • Pyruvate Dehydrogenase Complex
  • Lactic Acid
  • Acetyl Coenzyme A
  • Pyruvic Acid
  • Dichloroacetic Acid

Grants and funding

Dr. Kaynar received research grant support from NIH (HL126711). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Kaynar received salary support from NIH (HL126711).