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Embryonal erythropoiesis and aging exploit ferroptosis.
Redox Biol. 48:102175 (2021)
Ferroptosis is a form of regulated cell necrosis, as a consequence of Fe(II)-dependent lipid peroxidation. Although ferroptosis has been linked to cancer cell death, neurodegeneration and reperfusion injury, physiological roles of ferroptosis have not been elucidated to date mostly due to the lack of appropriate methodologies. Here, we show that 4-hydroxy-2-nonenal (HNE)-modified proteins detected by a HNEJ-1 mouse monoclonal antibody is a robust immunohistochemical technology to locate ferroptosis in tissues in combination with morphological nuclear information, based on various models of ferroptosis, including erastin-induced cysteine-deprivation, conditional Gpx4 knockout and Fe(II)-dependent renal tubular injury, as well as other types of regulated cell death. Specificity of HNEJ-1 with ferroptosis was endorsed by non-selective identification of HNE-modified proteins in an Fe(II)-dependent renal tubular injury model. We further comprehensively searched for signs of ferroptosis in different developmental stages of Fischer-344 rats from E9.5-2.5 years of age. We observed that there was a significant age-dependent increase in ferroptosis in the kidney, spleen, liver, ovary, uterus, cerebellum and bone marrow, which was accompanied by iron accumulation. Not only phagocytic cells but also parenchymal cells were affected. Epidermal ferroptosis in ageing SAMP8 mice was significantly promoted by high-fat or carbohydrate-restricted diets. During embryogenesis of Fischer-344 rats, we found ferroptosis in nucleated erythrocytes at E13.5, which disappeared in enucleated erythrocytes at E18.5. Administration of a ferroptosis inhibitor, liproxstatin-1, significantly delayed erythrocyte enucleation. Therefore, our results demonstrate for the first time the involvement of ferroptosis in physiological processes, such as embryonic erythropoiesis and aging, suggesting the evolutionally acquired mechanism and the inevitable side effects, respectively.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
4-hydroxy-2-nonenal ; Aging ; Erythropoiesis ; Ferroptosis ; Iron; Glutathione-peroxidase 4; Renal-cell Carcinoma; Oxidative Stress; Cancer-cells; Wistar Rats; Iron; Death; Carcinogenesis; Induction; Nitrilotriacetate
ISSN (print) / ISBN
2213-2317
e-ISSN
2213-2317
Journal
Redox Biology
Quellenangaben
Volume: 48,
Article Number: 102175
Publisher
Elsevier
Publishing Place
Amsterdam [u.a.]
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Metabolism and Cell Death (MCD)
Grants
European Research Council (ERC) under the European Union
Ministry of Science and Higher Education of The Russian Federation
JST CREST
JSPS KAKENHI
Deutsche Forschungsgemeinschaft (DFG)
Ministry of Science and Higher Education of The Russian Federation
JST CREST
JSPS KAKENHI
Deutsche Forschungsgemeinschaft (DFG)