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

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.

SUBMITTER: Bakalov V

PROVIDER: S-EPMC7643993 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Bakalov Veli V Reyes-Uribe Laura L Deshpande Rahul R Maloy Abigail L AL Shapiro Steven D SD Angus Derek C DC Chang Chung-Chou H CH Le Moyec Laurence L Wendell Stacy Gelhaus SG Kaynar Ata Murat AM

PloS one 20201105 11

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 ...[more]

PMID: 33151963

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Project description:IntroductionVascular leakage plays a vital role in sepsis-induced multi-organ dysfunction. Currently, no specific measures are available for vascular leakage. Ferroptosis, as a recently recognized form of cell death, plays a crucial role in cell dysfunction. It is still unknown whether ferroptosis participates in the occurrence of organ dysfunction following sepsis. Our previous study showed that dexmedetomidine (Dex) could alleviate sepsis-induced organ dysfunction. However, whether the mechanism is related to ferroptosis is not clear.MethodsThe publicly available datasets of septic patients were reanalyzed, and septic models in vivo and vitro by cecal ligation and puncture and lipopolysaccharide-stimulated vascular endothelial cells (VECs) were applied. The occurrence of ferroptosis in septic patients and rats was observed, and the protective effects of Dex on ferroptosis, and related mechanisms on regulating metabolic reprogramming and mitochondrial fission were further studied.ResultsThe transcriptomics data of patients from the GEO database showed that ferroptosis was closely related to sepsis. Sepsis induced significant ferroptosis in VECs by metabolomics analysis. The level of lipid peroxidation was increased in VECs, and the mitochondrial cristae was decreased after sepsis. Metabolomics analysis showed that Dex activated the pentose phosphate pathway and increased glutathione in VECs via up-regulation of G6PD expression. Dex could antagonize sepsis-induced the decrease in the level of Nrf2. The Nrf2 inhibitor reversed the protective effect of Dex on ferroptosis. Further study showed that Dex significantly alleviated sepsis-induced mitochondrial over-division, improved mitochondrial function, and decreased ROS, further inhibiting the ferroptosis of VECs. Dex alleviated the permeability of vessels by reducing ferroptosis and enhanced the intercellular junction of VECs.ConclusionDex protects vascular leakage following sepsis by inhibiting ferroptosis. The mechanism is mainly related to metabolic reprogramming via Nrf2 up-regulation and inhibition of mitochondrial fission.

Dataset Information

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

Publications

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

Similar Datasets

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