2. Academic Validation
  3. Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development

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

  • Nat Commun. 2024 Sep 1;15(1):7611. doi: 10.1038/s41467-024-51996-1.
Juliane Tschuck # 1,  Vidya Padmanabhan Nair # 2,  Ana Galhoz 3 4,  Carole Zaratiegui 5,  Hin-Man Tai 2,  Gabriele Ciceri 6,  Ina Rothenaigner 1,  Jason Tchieu 6 7,  Brent R Stockwell 8,  Lorenz Studer 6,  Daphne S Cabianca 5,  Michael P Menden 3 9,  Michelle Vincendeau 10 11,  Kamyar Hadian 12
Affiliations

Affiliations

  • 1 Research Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, Germany.
  • 2 Endogenous Retrovirus Group, Institute of Virology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 3 Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • 4 Department of Biology, Ludwig-Maximilians University Munich, Munich, Germany.
  • 5 Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 6 Developmental Biology and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 UC Department of Pediatrics, Division of Developmental Biology, Cincinnati Children's Hospital Medical, Cincinnati, OH, USA.
  • 8 Department of Biological Sciences, Department of Chemistry, Herbert Irving Comprehensive Cancer Center, Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA.
  • 9 Department of Biochemistry and Pharmacology, University of Melbourne, Parkville Victoria, Australia.
  • 10 Endogenous Retrovirus Group, Institute of Virology, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
  • 11 Technical University of Munich, Institute of Virology, School of Medicine, Munich, Germany. [email protected].
  • 12 Research Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
  • # Contributed equally.
PMID: 39218970 DOI: 10.1038/s41467-024-51996-1
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.

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