Sepsis, pyruvate, and mitochondria energy supply chain shortage

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.

A New Role of NAP1L1 in Megakaryocytes and Human Platelets

“…With PDC-E2 being an integral part of the mitochondrial pyruvate dehydrogenase complex, we started exploring functional consequences of the NAP1L1–PDC-E2 interaction. Several studies demonstrated that the mitochondrial pyruvate dehydrogenase complex gets dysregulated due to septic host environment [ 58 , 59 ]. Although anucleate, emerging data demonstrates that the human PLT transcriptome is not static.…”

“…The immunometabolism during sepsis is characterized by a switch from a high-energy infection resistance mode to a low-energy conservation tolerance mode within 4–8 h after sepsis dissemination [ 58 ]. The pyruvate dehydrogenase complex acts as an energy homeostat, and its deactivation creates an energy supply chain shortage during sepsis.…”

“…However, PDH complex activity increased 13-fold over the metabolic activity measured in PLTs isolated from healthy individuals. This finding could be met with surprise since published studies indicate that the PDH complex is inhibited during sepsis, resulting in a switch from mitochondrial aerobic oxidation to cytoplasmic anaerobic glycolysis, a process known to contribute to the formation of lactic acid and intracellular acidosis, which can lead to intracellular Ca2 + overload, mitochondrial membrane damage [ 58 , 82 , 83 ]. Nevertheless, contrasting the general PDC-dependent metabolic reprogramming response in sepsis [ 58 , 84 , 85 ], several studies demonstrated that mitochondrial oxygen consumption in PLTs is increased in septic patients, and closely related to their survival rate [ 86 , 87 , 88 ].…”

“…This finding could be met with surprise since published studies indicate that the PDH complex is inhibited during sepsis, resulting in a switch from mitochondrial aerobic oxidation to cytoplasmic anaerobic glycolysis, a process known to contribute to the formation of lactic acid and intracellular acidosis, which can lead to intracellular Ca2 + overload, mitochondrial membrane damage [ 58 , 82 , 83 ]. Nevertheless, contrasting the general PDC-dependent metabolic reprogramming response in sepsis [ 58 , 84 , 85 ], several studies demonstrated that mitochondrial oxygen consumption in PLTs is increased in septic patients, and closely related to their survival rate [ 86 , 87 , 88 ]. Therefore, based on our observations, we speculate that due to its chaperone and potential shuttling function, NAP1L1 protein in septic PLTs could help stabilize the conformation of PDC-E2 molecules, and also mediate the known one-way transport [ 89 ] into the mitochondrial compartment.…”

Metabolic Reprogramming and Its Regulatory Mechanism in Sepsis-Mediated Inflammation

“…In a septic mouse model, DCA treatment was found to reverse shock, reduce hepatocyte injury, significantly improve hyperlactatemia and immune paralysis, and significantly improve septic survival. 75 Mitochondrial homeostasis plays a decisive role in regulating cellular energy metabolism and signaling pathways. PPAR-γ coactivator 1 alpha (PGC-1α) is one of the most important transcription factors that can drive mitochondrial biogenesis to respond to external stimuli and maintain mitochondrial homeostasis.…”