Ferroptosis is an iron-dependent, oxidative cell death pathway implicated in tumor suppression and pathological cell death. This process is biochemically distinct from apoptosis, classic necrosis and iron overload-induced cell death. How ferroptosis is regulated at the molecular level is poorly understood. Guided by preliminary data, this research will test the hypotheses that ferroptosis is regulated by mechanistic target of rapamycin (mTOR) signaling and neutral lipid synthesis. Moreover, imaging studies using existing and newly discovered antioxidant inhibitors of ferroptosis will pinpoint the cellular sites of lethal iron-dependent lipid reactive oxygen species (ROS) accumulation during ferroptosis and examine how this accumulation is affected by mTOR signaling and neutral lipid synthesis. These studies will be performed in human cells with the aid of a novel time-lapse cell death imaging system and techniques drawn from chemical biology, genetics and biochemistry. This research will advance the understanding of ferroptosis at the molecular and cellular levels and lay the foundation for future in vivo studies of this poorly understood cell death process.

Public Health Relevance

The proposed studies will investigate the regulation of ferroptosis, a new non-apoptotic cell death pathway. This knowledge will enhance our understanding of this fundamental biological process and potentially identify new ways to manipulate this pathway therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM122923-02
Application #
9557514
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2017-09-05
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Tarangelo, Amy; Magtanong, Leslie; Bieging-Rolett, Kathryn T et al. (2018) p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells. Cell Rep 22:569-575
Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486-541
Dovey, Cole M; Diep, Jonathan; Clarke, Bradley P et al. (2018) MLKL Requires the Inositol Phosphate Code to Execute Necroptosis. Mol Cell 70:936-948.e7
Inde, Zintis; Dixon, Scott J (2018) The impact of non-genetic heterogeneity on cancer cell death. Crit Rev Biochem Mol Biol 53:99-114
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285