Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes

Lampl, Sandra; Janas, Marianne K.; Donakonda, Sainitin; Brugger, Marcus; Lohr, Kerstin; Schneider, Annika; Manske, Katrin; Sperl, Laura E.; Klaeger, Susan; Kuester, Bernhard; Wettmarshausen, Jennifer; Müller, Constanze; Laschinger, Melanie; Hartmann, Daniel; Hueser, Norber; Perocchi, Fabiana; Schmitt-Kopplin, Philippe; Hagn, Franz; Zender, Lars; Hornung, Veit; Borner, Christoph; Pichlmair, Andreas; Kashkar, Hamid; Klingenspor, Martin; Prinz, Marco; Schreiner, Sabrina; Conrad, Marcus; Jost, Philipp J.; Zischka, Hans; Steiger, Katja; Kroenke, Martin; Zehn, Dietmar; Protzer, Ulrike; Heikenwaelder, Mathias; Knolle, Percy A.; Wohlleber, Dirk (2020): Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. In: Journal of Hepatology, Vol. 73, No. 6: pp. 1347-1359

Abstract

Background: & Aims: Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism. Methods: We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests. Results: We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation. Conclusion: Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition. Lay summary: The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Research Centers: Center for Integrated Protein Science Munich (CIPSM)
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0168-8278
• Language: English