Title:Cerebral Ischemia Induces Iron Deposit, Ferritin Accumulation, Nuclear
Receptor Coactivator 4-depletion, and Ferroptosis
Volume: 19
Issue: 1
Author(s): Nora Hanke and Abdelhaq Rami*
Affiliation:
- Institut für Experimentelle Neurobiologie (Anatomie II), Klinikum der Johann Wolfgang von Goethe-Universität, Theodor-
Stern-Kai 7, 60590 Frankfurt/Main, Germany
Keywords:
Cerebral ischemia, ferroptosis, ferritin, ferritinophagy, GPX-4, NCOA4.
Abstract:
Background: The neuronal death upon cerebral ischemia shares not only characteristics
of necrosis, apoptosis, and autophagy but also exhibits biochemical and morphological characteristics
of ferroptosis. Ferroptosis is a regulated form of cell death that is considered to be an oxidative
iron-dependent process. It is now commonly accepted that iron and free radicals are considered to
cause lipid peroxidation as well as the oxidation of proteins and nucleic acids, leading to increased
membrane and enzymatic dysfunction and finally contributing to cell death. Although ferroptosis
was first described in cancer cells, emerging evidence now links mechanisms of ferroptosis to many
different diseases, including cerebral ischemia.
Methods: The objective of this study was to identify the key players and underlying biochemical
pathways of ferroptosis, leading to cell death upon focal cerebral ischemia in mice by using immunofluorescence,
Western blotting, histochemistry, and densitometry.
Results: In this study, we demonstrated that cerebral ischemia induced iron-deposition, downregulated
dramatically the expression of the glutathione peroxidase 4 (GPX4), decreased the expression
of the nuclear receptor coactivator 4 (NCOA4), and induced inappropriate accumulation of
ferritin in the ischemic brain. This supports the hypothesis that an ischemic insult may induce ferroptosis
through inhibition of GPX4.
Conclusion: We conclude that iron excess following cerebral ischemia leads to cell death despite
activating compensatory mechanisms for iron homeostasis, as illustrated by the accumulation of
ferritins. These data emphasized the presence of a cellular mechanism that allows neuronal cells to
buffer iron levels.
