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.
Keywords:
Glucose metabolism; Homeostasis; Immunology; Infectious disease; Mitochondria.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cells, Cultured
-
Dichloroacetic Acid / pharmacology*
-
Dichloroacetic Acid / therapeutic use
-
Disease Models, Animal
-
Drug Evaluation, Preclinical
-
Energy Metabolism / drug effects
-
Energy Metabolism / immunology
-
Homeostasis / drug effects
-
Homeostasis / immunology
-
Humans
-
Kaplan-Meier Estimate
-
Male
-
Mice
-
Mitochondria / drug effects
-
Mitochondria / immunology
-
Mitochondria / metabolism
-
Monocytes / cytology
-
Monocytes / immunology
-
Monocytes / metabolism
-
Primary Cell Culture
-
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / antagonists & inhibitors*
-
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
-
Pyruvate Dehydrogenase Complex / metabolism*
-
Sepsis / drug therapy*
-
Sepsis / immunology
-
Sepsis / mortality
-
Signal Transduction / drug effects
-
Signal Transduction / immunology
-
Treatment Outcome
Substances
-
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
-
Pyruvate Dehydrogenase Complex
-
Dichloroacetic Acid