Mitochondrial biogenesis in inflammation and sepsis

Sepsis is a systemic inflammatory response of the body to infection and represents the major cause of death in intensive care units. Recent data identified mitochondrial damage, mediated in part by components of the immune system, as a pathologic feature of tissues during sepsis. We hypothesise that regeneration of mitochondria and restoration of oxidative phosphorylation may improve recovery from sepsis. In this project we will study mitochondrial dysfunction and biogenesis in bone marrow-derived murine macrophages upon classical activation with lipopolysaccharide and interferon-?. Based on preliminary data we expect nitric oxide (NO), produced by inducible nitric oxide synthase, to play a critical role in both of these processes. We will employ state-of-the-art molecular biology, genetic and pharmacological tools to define the role of NO, to elucidate underlying signalling pathways and to study the consequences of mitochondrial biogenesis for macrophage survival. As an increasing number of major human pathologies are being related to chronic low-grade inflammation and mitochondrial dysfunction the proposed work has broad (patho )physiological and clinical implications.