B08: Brunner

The liver plays a pivotal role in nutrient storage and metabolism. It is, however, also exposed to uncontrolled immune reactions and toxic activities of various drugs, which may cause excessive hepatocyte death and liver damage. Various liver-damaging compounds either promote apoptotic or necrotic cell death. Interestingly, we have previously seen that members of the TNF family, i.e. TNF and TRAIL fail to promote directly hepatocyte death, yet strongly enhance cell death induction by triggers of mitochondrial outer membrane permeabilization, irrespective of the subsequent form of cell death. Similarly, there is a strong contribution of BCL-2 family members also in caspase-independent forms of necrosis. In this project, we aim to understand whether the crosstalk between TNF members and mitochondrial cell death triggers is a general phenomenon, with decisions for either apoptotic or necrotic outcomes. We will further elucidate the role of the BCL-2 interactome in the decision-making processes during this synergistic form of liver cell death. Specifically, we will investigate canonical activities of BCL-2 family members in the regulation of the intrinsic apoptosis pathway, resp. non-canonical activities in the regulation of cellular energy metabolism. Lastly, we aim to understand by which mechanisms TNF members enhance liver cell death, and whether they affect cellular decisions in between apoptotic and necrotic cell death modalities. A detailed understanding of the underlying mechanisms may result in new therapies against drug-induced liver damage and failure.

Publications

• Lambrecht R, Delgado ME, Gloe V, Schuetz K, Plazzo AP, Franke B, San Phan T, Fleming J, Mayans O, Brunner T. Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death. Cell Rep. 2023 Dec 26;42(12):113513. doi: 10.1016/j.celrep.2023.113513. Epub 2023 Nov 30. PMID: 38039134.
• Lambrecht R, Rudolf F, Ückert AK, Sladky VC, Phan TS, Jansen J, Naim S, Kaufmann T, Keogh A, Kirschnek S, Mangerich A, Stengel F, Leist M, Villunger A, Brunner T. Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis. Cell Death Differ. 2024 Jan;31(1):119-131. doi: 10.1038/s41418-023-01245-7. Epub 2023 Nov 24. PMID: 38001256; PMCID: PMC10781779.