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.
Charles E. McCall, Manal Zabalawi, Tiefu Liu, Ayana Martin, David L. Long, Nancy L. Buechler, Rob J. W. Arts, Mihai Netea, Barbara K. Yoza, Peter W. Stacpoole, Vidula Vachharajani
Dichloroacetate (DCA) reverses immune repressor and activator cytokines in the spleen of septic mice.