Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis
Autor: | Sylvia Krippner, Carsten Culmsee, Wibke E. Diederich, Anja Jelinek, Matthias Plessner, Lukas Heyder, Michael Daude, Robert Grosse |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Programmed cell death Ubiquinone Mitochondrion GPX4 Biochemistry Antioxidants Cell Line Lipid peroxidation Mice 03 medical and health sciences chemistry.chemical_compound Organophosphorus Compounds Physiology (medical) Animals Neurons chemistry.chemical_classification Glutathione Peroxidase Reactive oxygen species MitoQ Cell Death Glutathione peroxidase Glutathione Fibroblasts Phospholipid Hydroperoxide Glutathione Peroxidase Mitochondria Cell biology 030104 developmental biology chemistry BH3 Interacting Domain Death Agonist Protein Carbolines |
Zdroj: | Free Radical Biology and Medicine. 117:45-57 |
ISSN: | 0891-5849 |
Popis: | Research into oxidative cell death is producing exciting new mechanisms, such as ferroptosis, in the neuropathologies of cerebral ischemia and hemorrhagic brain insults. Ferroptosis is an oxidative form of regulated necrotic cell death featuring glutathione (GSH) depletion, disrupted glutathione peroxidase-4 (GPX4) redox defense and detrimental lipid reactive oxygen species (ROS) formation. Further, our recent findings identified mitochondrial damage in models of oxidative glutamate toxicity, glutathione peroxidase depletion, and ferroptosis. Despite knowledge on the signaling pathways of ferroptosis increasing, the particular role of mitochondrial damage requires more in depth investigation in order to achieve effective treatment options targeting mitochondria. In the present study, we applied RSL3 to induce ferroptosis in neuronal HT22 cells and mouse embryonic fibroblasts. In both cell types, RSL3 mediated concentration-dependent inhibition of GPX4, lipid peroxidation, enhanced mitochondrial fragmentation, loss of mitochondrial membrane potential, and reduced mitochondrial respiration. Ferroptosis inhibitors, such as deferoxamine, ferrostatin-1 and liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the BID inhibitor BI-6c9 protected against RSL3 toxicity. We found compelling new information that the mitochondria-targeted ROS scavenger mitoquinone (MitoQ) preserved mitochondrial integrity and function, and cell viability despite significant loss of GPX4 expression and associated increases in general lipid peroxidation after exposure to RSL3. Our data demonstrate that rescuing mitochondrial integrity and function through the inhibition of BID or by the mitochondria-targeted ROS scavenger MitoQ serves as a most effective strategy in the prevention of ferroptosis in different cell types. These findings expose mitochondria as promising targets for novel therapeutic intervention strategies in oxidative cell death. |
Databáze: | OpenAIRE |
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