Project Details
Projekt
Mechanisms of ferroptosis resistance in brown adipose tissue
Applicant
Professor Dr. Alexander Bartelt
Subject Area
Cell Biology
Biochemistry
Biochemistry
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461705523
Ferroptosis is an emerging novel mechanism of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the physiological background of ferroptosis remains obscure. This proposal is built on our finding that brown adipocytes, mammalian fat cells that naturally display unique oxidative metabolism for heat generation in response to cold, are characterized by several hallmarks of ferroptosis, yet these cells are surprisingly resistant. This suggests that brown adipocytes potentially possess specialized molecular mechanisms in order to prevent or resist ferroptosis despite the high exposure to ferroptosis-inducing factors. Our preliminary data show that diminished proteasomal protein quality control, the elimination of obsolete or damaged proteins, is a new mechanistic feature of ferroptosis, and that the transcription factor Nuclear factor erythroid-2, like-1 (Nfe2l1) physiologically protects brown adipocytes from ferroptosis by sustaining high proteasomal activity. This project will investigate anti-ferroptotic defense mechanisms in brown adipose tissue under natural as well as under experimental ferroptotic conditions in mice by employing a global ubiquitomic and oxilipidomic strategy as well as defining the labile iron pool. Using CRISPR-Cas9-engineered brown adipocyte cell lines we will delineate the mechanistic basis of ferroptosis resistance and the role of Nfe2l1-mediated proteasomal protein quality control in this process. Finally, we have established transgenic mouse models for the brown adipocyte-specific loss- and gain-of-function of Nfe2l1 in the absence or presence of glutathione peroxidase-4 (Gpx4) so that we now can determine the physiologic role of ferroptosis resistance for energy metabolism and systemic metabolic health exemplified here for brown adipocytes as a model system. In summary, this project will seamlessly and synergistically add value to the DFG Priority Program SPP 2306, as our approach will define novel physiologic pathways and metabolic networks directly regulating ferroptosis and susceptibility to lipid peroxidation, as well as introducing proteasomal protein quality control as a novel molecular mechanism of ferroptosis sensitivity and its pathophysiological consequences.
DFG Programme
Priority Programmes
