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

• Published in: The FEBS journal Vol. 289; no. 13; pp. 3894 - 3914
• Main Authors: Ledahawsky, Leire M., Terzenidou, Maria Eirini, Edwards, Ruairidh, Kline, Rachel A., Graham, Laura C., Eaton, Samantha L., Hoorn, Dinja, Chaytow, Helena, Huang, Yu‐Ting, Groen, Ewout J. N., Motyl, Anna A. L., Lamont, Douglas J., Tokatlidis, Kostas, Wishart, Thomas M., Gillingwater, Thomas H.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2022
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Alzheimer's disease; Animals; Caspase; Cation Transport Proteins - metabolism; Cell death; Dopamine receptors; Mice; Mitochondria; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Movement disorders; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurodegeneration; Neurodegenerative diseases; Parkinson Disease - pathology; Parkinson's disease; Proteins; Proteomics; Sideroflexin 3; synapse; Synapses; Synapses - metabolism; Synuclein; Therapeutic targets; neurodegeneration; Sideroflexin 3; Parkinson's disease; synapse; mitochondria
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16377

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). Overexpression 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. SFXN3 is a neuronally enriched mitochondrial protein found at the synapse. Here, we show that SFXN3 influences expression levels of neurodegeneration and cell death‐associated proteins in mice, that its overexpression provides neuroprotection at the synapse in Drosophila models of Parkinson's disease, but that its absence or downregulation is insufficient to trigger neurodegeneration in mice and Drosophila.