Project Details
Projekt
Mechanisms of organ resistance and susceptibility to ferroptosis in a disease model of iron overload
Applicant
Professorin Dr. Martina Muckenthaler
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461704553
Ferroptosis is defined as an iron-dependent form of regulated cell death leading to the lethal accumulation of lipid-based reactive oxygen species (ROS). Iron exerts multiple effects in the ferroptosis process, which include redox-dependent and redox-independent functions. So far, little is known how impairment of iron-regulatory mechanisms at the level of an entire organism contribute to ferroptosis. In our previous work, we have generated a mouse model with a disruption of the hepcidin/ferroportin regulatory axis [Fpn(C326S) mice] that maintains systemic iron homeostasis. These mice reflect well upon the pathophysiology of human hereditary hemochromatosis type 4 and show high levels of iron overload, including elevated plasma iron and ferritin levels, high transferrin saturation and tissue iron overload. Unlike other mouse models of iron overload, homozygous Fpn(C326S) mice die between 7 and 14 months of age involving ferroptosis of the pancreas. An interesting observation in Fpn(C326S) mice is that some tissues (e.g. the pancreas) are severely damaged by iron overload, while others (e.g. the liver) are less affected, although both tissues accumulate similarly high levels of iron causing similar levels of lipid peroxidation. The overall aim of this proposal is to understand how iron impacts on ferroptosis and viability in a mouse model of iron overload disease. We aim to identify mechanisms that protect (e.g. the liver) or sensitize (e.g. the pancreas) organs for iron-induced damage. We will further compare molecular signatures of iron-induced ferroptosis with “classic” ferroptosis models. We expect that the data obtained will contribute to identify biomarkers for ferroptosis sensitivity induced by iron overload. These results will help to determine which of the anti-ferroptosis therapies currently in development may be applicable to prevent tissue damage in iron overload disorders.
DFG Programme
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