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- Title
Sepsis, pyruvate, and mitochondria energy supply chain shortage.
- Authors
McCall, Charles E.; Zhu, Xuewei; Zabalawi, Manal; Long, David; Quinn, Matthew A.; Yoza, Barbara K.; Stacpoole, Peter W.; Vachharajani, Vidula
- Abstract
Balancing high energy‐consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.
- Subjects
PYRUVATE dehydrogenase complex; POWER resources; SEPSIS; SUPPLY chains; PYRUVATES; MITOCHONDRIA; VAGINAL contraceptives
- Publication
Journal of Leukocyte Biology, 2022, Vol 112, Issue 6, p1509
- ISSN
0741-5400
- Publication type
Article
- DOI
10.1002/JLB.3MR0322-692RR