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.

Nonhormonal therapy for endometriosis based on energy metabolism regulation

“…In particular, the metabolic shift may be an attractive target for nonhormone-based endometriosis treatment. Treatment strategies that utilize metabolic reprogramming are implemented not only in cancer but also in sepsis ( Bakalov et al 2020 ), schizophrenia ( Pruett & Meador-Woodruff 2020 ), autoimmune disease ( Kornberg 2020 ), or mitochondrial disease ( Kobayashi et al 2021 a ).…”

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

“…The expression levels of hexokinase 2 (HK2)—which catalyzes the first step of glycolysis [ 32 ]—and pyruvate kinase muscle form 2 (PKM2)—which catalyzes the last step of glycolysis [ 33 ]—increased in LTZ-rats compared to those in Veh-rats (HK2, 1.82-fold, p < 0.05) (PKM2, 1.42-fold, p < 0.05) ( Figure 4 A). Additionally, the expression of pyruvate dehydrogenase (PDH)—the enzyme that converts pyruvate to acetyl-CoA [ 34 , 35 ]—also increased in LTZ-rats compared to Veh-rats (2.03-fold, p < 0.05) ( Figure 4 A). From an in vitro assay using the H9c2 cell line, the expression levels of HK2, PKM2, and PDH were found to be higher in LTZ-cells compared to those in Veh-cells (HK2, 2.00-fold, p < 0.05) (PKM2, 1.24-fold, p < 0.05) (PDH, 1.86-fold, p < 0.05) ( Figure 4 B).…”

The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy

“…As mentioned above, PDHC is a critical regulator of lactate levels. Bakalov et al ( 20 ) confirmed that sepsis could lead to decreased PDHC activity and increased lactic acid levels in the gross tissues of Drosophila, while the upregulation of PDHC activity could reduce lactic acid levels and improve the survival rate of the flies. In a rat model of sepsis, inhibiting PDHC activity can lead to a significant increase in the level of lactate, illustrating the negative regulatory effect exerted by PDHC activity on the level of lactic acid ( 37 ).…”

“…This finding highlights that PDK inhibition exerts positive regulatory effects in glycolysis via PDHC, allowing M1 macrophages to be polarized toward the M2 phenotype, thus tempering the release of inflammatory mediators ( 42 ). Bakalov et al showed that PDHC activation led to the lowered level of cecropin-A and defensin, two releasing markers of pro-inflammatory factors, resulting in the improvement of life span of septic Drosophila ( 20 ). These results indicate that regulation of PDHC activity may represent a therapeutic target in the treatment of sepsis.…”

“…A large number of studies have focused on PDHC, the key regulator of glucose metabolism, in exploring the underlying pathogenesis of sepsis ( 20 ). Accordingly, PDHC has been shown to regulate critical processes, including lactate production, the release of inflammatory mediators, TCA cycle, lipid metabolism and energy production.…”