LONGEVITIES: LONG-term Effects of renal mitochondrial Vitality in severe InfEctions and Sepsis
Mitochondrial dysfunction during sepsis mainly results from injury induced by free radicals (nitration and oxidation), which are generated as toxic by-product of mitochondrial respiration. In order to match the higher ATP demand during sepsis, mitochondrial respiration initially increases, leading to a doubling of cellular oxygen consumption and a higher production rate of ATP, but also to increased generation of free radicals. Currently, it is not known whether mitochondrial damage in the kidney is repaired after survival form sepsis. Damage to mitochondria may permanently affect mitochondrial function and impair long-term health span and lifespan after sepsis. In line with this hypothesis, mitochondrial function in muscle cells is not restored after sepsis and is associated with a lowered number of mitochondria. Analogue to the process of aging, sepsis is associated with a reduced mitochondrial function and increased levels of free radicals. Molecular signs of mitochondrial damage upon aging are associated with CKD and important co-morbidities such as diabetes mellitus type 2, and cardiovascular diseases. Furthermore, biomarkers for a reduced mitochondrial function, including inactivation of complex IV in peripheral blood mononuclear cells and increased free radical formation are associated with the development of CKD. Whether a similar correlation between mitochondrial function and CKD exists among sepsis survivors remain to be unraveled. Potentially, oxidative stress during sepsis induces a comparable aged mitochondrial phenotype and thereby increases the risk of CKD, cardiovascular events, aging-related diseases and mortality after survival from sepsis. Thus, prevention of mitochondrial damage may not only preclude AKI and improve short-term survival, but also maintain renal function and improve long-term survival after sepsis.
Financial support: Dutch Kidney Foundation