Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development

Juliane Tschuck, Vidya Padmanabhan Nair, Ana Galhoz, Carole Zaratiegui, Hin-Man Tai, Gabriele Ciceri, Ina Rothenaigner, Jason Tchieu, Brent R. Stockwell, Lorenz Studer, Daphne S. Cabianca, Michael P. Menden, Michelle Vincendeau () and Kamyar Hadian ()
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Juliane Tschuck: Helmholtz Zentrum München
Vidya Padmanabhan Nair: Helmholtz Zentrum München
Ana Galhoz: Helmholtz Zentrum München
Carole Zaratiegui: Helmholtz Zentrum München
Hin-Man Tai: Helmholtz Zentrum München
Gabriele Ciceri: Memorial Sloan Kettering Cancer Center
Ina Rothenaigner: Helmholtz Zentrum München
Jason Tchieu: Memorial Sloan Kettering Cancer Center
Brent R. Stockwell: Columbia University
Lorenz Studer: Memorial Sloan Kettering Cancer Center
Daphne S. Cabianca: Helmholtz Zentrum München
Michael P. Menden: Helmholtz Zentrum München
Michelle Vincendeau: Helmholtz Zentrum München
Kamyar Hadian: Helmholtz Zentrum München

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.

Date: 2024
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DOI: 10.1038/s41467-024-51996-1

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