Project Details
Projekt
Iron-induced pancreatic ferroptosis: Deciphering underlying mechanisms and clinical implications for iron overload disorders
Applicant
Professorin Dr. Martina Muckenthaler
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461704553
Ferroptosis is hallmarked by iron-dependent oxidation of polyunsaturated fatty acids (PUFA)-containing phospholipids and accumulation of lipid peroxides in cell membranes. Iron exerts both redox-dependent and redox-independent functions in the ferroptosis process. Our research aims to identify the mechanisms how iron accumulation in hemochromatosis causes selective organ damage, ferroptosis and lethality. We investigate in FpnC326S/C326S mice why the pancreas is sensitive to iron-induced ferroptosis and the liver is resistant – despite similar levels of iron content. In the last funding period we demonstrated that the vulnerability of pancreatic acinar cells to ferroptosis (compared to hepatocytes) is explained by their reduced capacity to export iron via ferroportin, causing a net-increase of non-transferrin-bound iron (NTBI) levels and thereby an increased challenge for the low-capacity ROS buffer typical for the pancreas. In cooperation with SPP2306 partners we showed that iron accumulation in the pancreas may induce epithelial to mesenchymal transition (EMT) and lipidome changes that may contribute to the increased ferroptosis sensitivity. Importantly, our data show that Gpx4, a prominent gatekeeper of ferroptosis is tuned down in the iron loaded pancreas. In the second funding period, we now aim to better understand the interaction of GPX4 and iron homeostasis. We will generate new mouse models (pancreatic GPX4 deficiency and overexpression) to validate the critical role of Gpx4 in the context of iron-induced ferroptosis. We will further assess whether Vitamin E dietary supplementation, which has previously been shown to compensate for GPX4 deficiency in liver and hematopoietic system, can protect FpnC326S/C326S mice from iron-induced ferroptosis in the pancreas. Finally, we will explore mechanisms responsible for decreased Gpx4 levels in the iron-loaded FpnC326S/C326S pancreas with the aim to identify druggable nodes. Overall, we will discover how iron overload induces organ-specific ferroptosis and identify novel mechanisms how the affected organ can be protected from iron-induced toxicity and ferroptosis. We expect that this knowledge will pave the way to develop therapeutic strategies to protect from pancreatic dysfunction in iron overload disorders.
DFG Programme
Priority Programmes
