Alteration of mitochondrial dynamics in acute pancreatitis

• Applicant: Dr. Lukas Zierke
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557850126

The pathogenesis of acute pancreatitis has been studied for decades. However, some parts are still unknown. The disease begins within the pancreatic acinar cells with a sustained increase in the cytosolic Ca2+ concentration. This can influence various intracellular pathways, such as the intracellular trypsin activation or transcription of the immunomodulatory transcription factor NFΚB. If the acinar cell cannot handle the several stress responses, cell death is induced, leading to the onset of acute pancreatitis. The mitochondrial contribution to the pathogenesis is of special interest because the regulation of ATP synthesis can influence multiple cellular pathways, control the type of cell death, and thus influence disease severity. Mitochondria have their own stress response: regulation of mitochondrial transcription, the mitochondrial unfolded protein response (UPR), or the degradation of damaged mitochondria through autophagy, also called mitophagy, for example. Processes that can influence these stress responses are the so-called mitochondrial fusion and fission. They can mediate the fusion of two or the fission of one mitochondria. Dysregulation of these processes is described for several diseases, which can lead to cytotoxic, but in some cases also protective effects. This project aims to investigate the balance of mitochondrial fusion and fission during acute pancreatitis. Therefore, multiple work packages are planned. In the beginning, the dynamics of these processes are analyzed in murine 266-6 cells and isolated acinar cells from mice. Therefore, not only wild-type cells but also cells with a knockout of several relevant proteins (DRP1 for fission, MFN1, MFN2, OMA1 and OPA1 for fusion) or cells isolated from mice with a pancreas-specific knockout of these proteins (DRP1, OMA1, or OPA1) will be used. Furthermore, the effect of fusion/fission regulators on these processes and the pathogenesis of the disease will be investigated in vitro in these cells. In the final work package, an investigation of the balance and modulation of mitochondrial fusion and fission in vivo will be carried out. Therefore, acute pancreatitis will be induced by the caerulein model in mice with a pancreas-specific knockout of DRP1, OMA1, or OPA1 as well as in wild-type mice with treatment with the most promising fusion/fission modulators. Ultimately, we aim to use in vitro and in vivo experiments to gain a better overview and understanding of the mitochondrial dynamics and their changes in acute pancreatitis, in particular their effects on the cellular stress response in vitro as well as the course and severity of the disease in vivo.

• DFG Programme: Research Grants