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

Author

Listed:
  • Veli Bakalov
  • Laura Reyes-Uribe
  • Rahul Deshpande
  • Abigail L Maloy
  • Steven D Shapiro
  • Derek C Angus
  • Chung-Chou H Chang
  • Laurence Le Moyec
  • Stacy Gelhaus Wendell
  • Ata Murat Kaynar

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.

Suggested Citation

  • Veli Bakalov & Laura Reyes-Uribe & Rahul Deshpande & Abigail L Maloy & Steven D Shapiro & Derek C Angus & Chung-Chou H Chang & Laurence Le Moyec & Stacy Gelhaus Wendell & Ata Murat Kaynar, 2020. "Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-18, November.
  • Handle: RePEc:plo:pone00:0241122
    DOI: 10.1371/journal.pone.0241122
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    References listed on IDEAS

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    1. Kazuhiko Yamane & Irene L Indalao & Junji Chida & Yoshikazu Yamamoto & Masaaki Hanawa & Hiroshi Kido, 2014. "Diisopropylamine Dichloroacetate, a Novel Pyruvate Dehydrogenase Kinase 4 Inhibitor, as a Potential Therapeutic Agent for Metabolic Disorders and Multiorgan Failure in Severe Influenza," PLOS ONE, Public Library of Science, vol. 9(5), pages 1-13, May.
    2. Oscar R. Colegio & Ngoc-Quynh Chu & Alison L. Szabo & Thach Chu & Anne Marie Rhebergen & Vikram Jairam & Nika Cyrus & Carolyn E. Brokowski & Stephanie C. Eisenbarth & Gillian M. Phillips & Gary W. Cli, 2014. "Functional polarization of tumour-associated macrophages by tumour-derived lactic acid," Nature, Nature, vol. 513(7519), pages 559-563, September.
    3. Liangchun Yang & Min Xie & Minghua Yang & Yan Yu & Shan Zhu & Wen Hou & Rui Kang & Michael T. Lotze & Timothy R. Billiar & Haichao Wang & Lizhi Cao & Daolin Tang, 2014. "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
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