Mitochondrial failure in sepsis: acute mechanisms and long-term consequences

Sepsis is defined as a dysregulated host response to infection, which can lead to loss of organ homeostasis and multiple organ failure. Mortality and morbidity associated with sepsis and septic shock are high. Sepsis causes one in five of all global deaths, which equals about 11 million deaths per year. Health problems and death rates after surviving sepsis also remain high. Despite years of research, little is known about the exact cause of organ failure in sepsis and treatment remains limited to antibiotics and supportive care. Mitochondria have emerged as key players in the pathogenesis of organ failure in sepsis. In this thesis, we explored the role of mitochondria in the induction of organ failure in sepsis. We found that sepsis leads to mitochondrial DNA damage, as can be measured in plasma and in the kidney. In addition, oxidative damage during sepsis is associated with long-term mortality and kidney failure. Experiments in cells and mice revealed that administration of hydrogen sulfide (H2S) protects mitochondria in cells and mice during sepsis, and lowers inflammation and kidney damage in mice. Further unravelling the role of mitochondria in sepsis can aid the development of novel therapies to improve mitochondrial function with major relevance to the health and life span of patients with sepsis.