A03: Wohlleber

Mitochondria are key organelles in cellular eneProject Leader: Dirk Wohlleberrgy metabolism. In several cell types, so-called type II cells like hepatocytes, mitochondria are also centrally involved in amplifying the caspase cascade after ligation of cell surface death receptors. Therefore, mitochondria are key hubs in orchestrating energy metabolism and cell death execution. Recently, we have shown that during viral infection, mitochondria in hepatocytes assume a so far unrecognized role in the decision whether TNF receptor 1 (TNFR1) stimulation leads to apoptosis or not. This decision is based on mitochondrial changes in stress resilience, i.e. the inability to return to a homeostatic state of metabolism after exposure to stress situations like Ca²⁺ challenges. This reduced stress resilience during viral infection tips the balance of physiological non-apoptotic signaling processes to pro-apoptotic decisions. Interestingly, this pro-apoptotic decision is independent of caspase 8, but rather is mediated by Ca²⁺ challenges of mitochondria by the ER after death receptor ligation. The mechanisms for this fundamental change in mitochondrial signaling are not understood. Preliminary data indicate that excessive (viral) gene expression leads to a loss of mitochondrial stress resilience, i.e. mitochondria undergo membrane permeability transition after Ca²⁺ challenges. In a first part, we will therefore characterize the relevance of viral gene expression and translation, and identify threshold levels for mitochondrial stress resilience. In a second part, we aim to identify metabolic or cellular changes leading to cell death decisions in the context of decreased mitochondrial resilience. And in a third part, we will identify molecular mechanisms that counteract pro-apoptotic signaling during infection with the clinically relevant hepatitis B virus. The overall goal of this proposal is to characterize cell-intrinsic mechanisms that allow for cell death induction in virus-infected hepatocytes upon death receptor stimulation. This knowledge will lead to a better understanding of antiviral immune surveillance.