Sideroflexin 3 is a α-synuclein-1 dependent mitochondrial protein 2 that regulates synaptic morphology

α-synuclein plays a central role in Parkinson’s disease, where it contributes to the vulnerability of synapses to degeneration. However, the downstream mechanisms through which α-synuclein controls synaptic stability and degeneration are not fully understood.
Here, comparative proteomics on synapses isolated from α-synuclein-/- mouse brain identified mitochondrial proteins as primary targets of α-synuclein, revealing mitochondrial proteins not previously linked to α-synuclein or neurodegeneration pathways. Of these, sideroflexin 3 (sfxn3) was found to be a mitochondrial protein localized to the inner mitochondrial membrane. Loss of sfxn3 did not disturb mitochondrial electron transport chain function in mouse synapses, suggesting that its function in mitochondria is likely independent of canonical bioenergetic pathways. In contrast, experimental manipulation of sfxn3 levels disrupted synaptic morphology at the Drosophila neuromuscular junction. These results provide novel insights into α-synuclein dependent pathways, highlighting an important influence on mitochondrial proteins at the synapse, including sfxn3. We also identify sfxn3 as a novel mitochondrial protein capable
of regulating synaptic morphology in vivo.