The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways in vivo

Leire M. Ledahawsky, Maria Eirini Terzenidou, Ruairidh Edwards, Rachel A. Kline, Laura C. Graham, Samantha L. Eaton, Dinja van der Hoorn, Helena Chaytow, Yu-Ting Huang, Ewout J. N. Groen, Anna A. L. Motyl, Douglas J. Lamont, Kostas Tokatlidis (Lead / Corresponding author), Thomas M. Wishart (Lead / Corresponding author), Thomas H. Gillingwater (Lead / Corresponding author)

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Abstract

Synapses are a primary pathological target in neurodegenerative diseases. Identifying therapeutic targets at the synapse could delay progression of numerous conditions. The mitochondrial protein SFXN3 is a neuronally-enriched protein expressed in synaptic terminals and regulated by key synaptic proteins, including α-synuclein. We first show that SFXN3 uses the carrier import pathway to insert into the inner mitochondrial membrane. Using high-resolution proteomics on Sfxn3-KO mice synapses, we then demonstrate that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSPα and Caspase-3), as well as neurological conditions (including Parkinson's disease and Alzheimer's disease). Over-expression of SFXN3 orthologues in Drosophila models of Parkinson's Disease significantly reduced dopaminergic neuron loss. In contrast, the loss of SFXN3 was insufficient to trigger neurodegeneration in mice, indicating an anti- rather than pro-neurodegeneration role for SFXN3. Taken together, these results suggest a potential role for SFXN3 in the regulation of neurodegeneration pathways.

Original languageEnglish
Pages (from-to)3894-3914
Number of pages21
JournalFEBS Journal
Volume289
Issue number13
Early online date28 Jan 2022
DOIs
Publication statusPublished - Jul 2022

Keywords

  • Parkinson's disease
  • Sideroflexin 3
  • mitochondria
  • neurodegeneration
  • synapse

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