Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

Tadokoro, Tomonori; Ikeda, Masataka; Ide, Tomomi; Deguchi, Hiroshi; Ikeda, Soichiro; Okabe, Kazuto; Ishikita, Ayako; Matsushima, Shouji; Koumura, Tomoko; Yamada, Ken Ichi; Imai, Hideki; Tsutsui, Hiroyuki

doi:10.1172/jci.insight.132747

Cited by 450 publications

(425 citation statements)

References 56 publications

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“…Fourth, dexrazoxane or ferrostatin-1 inhibits ferroptosis in a doxorubicin-induced cardiac injury model ( Fang et al, 2019 ). Of note, other studies suggest that Mito-FerroGreen (MFG, a fluorescence indicator specifically chelating Fe 2+ in mitochondria), but not dexrazoxane and DFO, prevents doxorubicin-induced lipid peroxidation and mitochondria-dependent ferroptosis in cardiomyopathy ( Tadokoro et al, 2020 ), indicating that mitochondrial iron may play a major role in mediating ferroptotic heart damage.…”

Section: Therapeutic Implications Of Iron Chelatorsmentioning

confidence: 99%

Iron Metabolism in Ferroptosis

Chen

Kang

et al. 2020

Front. Cell Dev. Biol.

594

382

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Ferroptosis is a form of regulated cell death that is characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures and the release of damage-associated molecular patterns. Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, ferroptosis is strictly controlled by regulators involved in many aspects of iron metabolism, such as iron uptake, storage, utilization, and efflux. Translational and transcriptional regulation of iron homeostasis provide an integrated network to determine the sensitivity of ferroptosis. Impaired ferroptosis is implicated in various iron-related pathological conditions or diseases, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. Understanding the molecular mechanisms underlying the regulation of iron metabolism during ferroptosis may provide effective strategies for the treatment of ferroptosis-associated diseases. Indeed, iron chelators effectively prevent the occurrence of ferroptosis, which may provide new approaches for the treatment of iron-related disorders. In this review, we summarize recent advances in the theoretical modeling of iron-dependent ferroptosis, and highlight the therapeutic implications of iron chelators in diseases.

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Section: Therapeutic Implications Of Iron Chelatorsmentioning

confidence: 99%

Iron Metabolism in Ferroptosis

Chen

Kang

et al. 2020

Front. Cell Dev. Biol.

594

382

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“…Since mitochondrial ROS act as signal-transducing molecules that upregulate inflammatory cytokines [ 158 ] in conditions with excessive inflammatory response, as happens in severe COVID-19 symptoms, it is expected that mitochondrial antioxidants such as mGSH would play a role during the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection. Chemotherapy—standard chemotherapeutic agents such as doxorubicin and cisplatin are well-known inducers of mitochondrial ROS during their anti-tumoral action [ 159 , 160 ]. However, the mitochondrial effects of other more recently approved anti-cancer drugs, such as sorafenib or regorafenib, are being just revealed [ 161 , 162 ].…”

Section: Mgsh In Pathological Settingsmentioning

confidence: 99%

“…Chemotherapy—standard chemotherapeutic agents such as doxorubicin and cisplatin are well-known inducers of mitochondrial ROS during their anti-tumoral action [ 159 , 160 ]. However, the mitochondrial effects of other more recently approved anti-cancer drugs, such as sorafenib or regorafenib, are being just revealed [ 161 , 162 ].…”

Section: Mgsh In Pathological Settingsmentioning

confidence: 99%

Mitochondrial Glutathione: Recent Insights and Role in Disease

et al. 2020

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Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox environment. mGSH’s ability to act directly or as a co-factor in reactions catalyzed by other mitochondrial enzymes makes its presence essential to avoid or to repair oxidative modifications that can lead to mitochondrial dysfunction and subsequently to cell death. Since mitochondrial redox disorders play a central part in many diseases, harboring optimal levels of mGSH is vitally important. In this review, we will highlight the participation of mGSH as a contributor to disease progression in pathologies as diverse as Alzheimer’s disease, alcoholic and non-alcoholic steatohepatitis, or diabetic nephropathy. Furthermore, the involvement of mitochondrial ROS in the signaling of new prescribed drugs and in other pathologies (or in other unmet medical needs, such as gender differences or coronavirus disease of 2019 (COVID-19) treatment) is still being revealed; guaranteeing that research on mGSH will be an interesting topic for years to come.

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“…This effect might be general, as it would potentiate the lipid peroxidation in ferroptosis induced by anthracyclins. However, potentiating ferroptosis may increase the cardiotoxicity of anthracyclins 68 . Paradoxically, it has been reported that PUFAs may have a cardioprotective effect in anthracyclin chemotherapy 69,70 .…”

Section: Perspectives In Metabochemotherapy and Anthracyclinsmentioning

confidence: 99%

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

Balgoma

Kullenberg

Calitz

et al. 2021

Preprint

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Metabolic and personalized interventions in cancer treatment require a better under-standing of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes of the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethano-lamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggests supplementa-tion with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depend-ing on the type of tumor and the individual. Finally, we discuss the changes in the lipidome in re-lation to the endoplasmic reticulum stress and the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

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Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

Cited by 450 publications

References 56 publications

Iron Metabolism in Ferroptosis

Iron Metabolism in Ferroptosis

Mitochondrial Glutathione: Recent Insights and Role in Disease

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

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