Augmenting Mitochondrial Function in Sepsis

Abstract Sepsis is a major cause of morbidity and mortality worldwide and is defined by the Sepsis-3 Task Force as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” The dysregulated response leads to cellular dysfunction and organ failure, including an inability for cells and tissues to use oxygen despite adequate systemic availability. Bioenergetics and metabolism have become an important focus of cellular dysfunction in sepsis, and mitochondrial dysfunction in sepsis is believed to contribute to organ failure. Mitochondrial ability to coordinate oxidative phosphorylation (OXPHOS) and sustain appropriate ATP production is impaired in sepsis, leading to increased dependence on glycolysis and elevated lactate levels3. Mitochondria are also central to modulating inflammatory pathways and the immune response to infection. Despite the evolution of the mechanistic understanding of mitochondrial failure in sepsis, the field still lacks effective therapeutics to target and modulate mitochondrial function in septic patients. The primary objective of this proposal is to test the ability of a novel mitochondria-augmenting compound, AuPhos, to improve outcomes in a murine sepsis model. Using a cecal slurry (CS)-induced sepsis model that includes repeated antibiotic and fluid administration, validated by the Starr Lab, we will assess the ability of AuPhos to improve animal survival, organ injury, and mitochondrial function. We will include blood samples from septic patients in our mitochondrial testing to increase the translational potential of these experiments.