Oligodendrocytes Provide Antioxidant Defense Function for Neurons by Secreting Ferritin Heavy Chain

Chaitali Mukherjee, Tina Kling, Belisa Russo, Kerstin Miebach, Eva Kess, Martina Schifferer, Liliana D. Pedro, Ulrich Weikert, Maryam K. Fard, Nirmal Kannaiyan, Moritz Rossner, Marie Louise Aicher, Sandra Goebbels, Klaus Armin Nave, Eva Maria Krämer-Albers, Anja Schneider, Mikael Simons

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

An evolutionarily conserved function of glia is to provide metabolic and structural support for neurons. To identify molecules generated by glia and with vital functions for neurons, we used Drosophila melanogaster as a screening tool, and subsequently translated the findings to mice. We found that a cargo receptor operating in the secretory pathway of glia was essential to maintain axonal integrity by regulating iron buffering. Ferritin heavy chain was identified as the critical secretory cargo, required for the protection against iron-mediated ferroptotic axonal damage. In mice, ferritin heavy chain is highly expressed by oligodendrocytes and secreted by employing an unconventional secretion pathway involving extracellular vesicles. Disrupting the release of extracellular vesicles or the expression of ferritin heavy chain in oligodendrocytes causes neuronal loss and oxidative damage in mice. Our data point to a role of oligodendrocytes in providing an antioxidant defense system to support neurons against iron-mediated cytotoxicity.

Original languageEnglish
Pages (from-to)259-272.e10
JournalCell Metabolism
Volume32
Issue number2
DOIs
StatePublished - 4 Aug 2020
Externally publishedYes

Keywords

  • axon-glia
  • ferritin
  • glia
  • iron
  • myelin
  • oligodendrocytes

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