Embryonal erythropoiesis and aging exploit ferroptosis

Hao Zheng; Li Jiang; Tsuyoshi Tsuduki; Marcus Conrad; Shinya Toyokuni

doi:10.1016/j.redox.2021.102175

Embryonal erythropoiesis and aging exploit ferroptosis

Redox Biol. 2021 Oct 30:48:102175. doi: 10.1016/j.redox.2021.102175. Online ahead of print.

Authors

Hao Zheng¹, Li Jiang¹, Tsuyoshi Tsuduki², Marcus Conrad³, Shinya Toyokuni⁴

Affiliations

¹ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
² Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1, Aoba, Aramaki, Aoba-ku, Sendai, 980-0845, Japan.
³ Helmholtz Zentrum München, Institute of Metabolism and Cell Death, 85764, Neuherberg, Germany; Pirogov National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, Moscow, 117997, Russia.
⁴ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp.

Abstract

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.

Keywords: 4-Hydroxy-2-nonenal; Aging; Erythropoiesis; Ferroptosis; Iron.