Alpha‐synuclein N‐ and C‐terminal regions have distinct in vivo roles in mitochondrial fragmentation and oxidation: Implications for a pathogenic mitochondrial pathway for Parkinson’s disease (PD)

Background Mitochondrial health depends on a critical balance between fission via dynamin‐related protein 1 (DRP1) and fusion via mitofusin (MFN) in concert to mitochondrial motility, and defects in fission‐fusion and motility are linked to neuronal dysfunction. In Parkinson’s disease (PD) which is characterized by progressive neuronal loss and α‐syn‐rich Lewy bodies, the presence of impaired mitochondrial function, fragmentation, and high oxidative stress are also seen. Methods Using genetics, in vivo reporters of mitochondrial health and biochemical analysis, here we test the physiological relevance of α‐syn in mitochondrial homeostasis using a Drosophila model of PD. Results Excess human α‐syn cause fragmented mitochondria, which are rescued by excess/depletion of DRP1, but not by excess MFN. Contrary to previous knowledge, α‐syn aggregation did not contribute to mitochondrial fragmentation as rescue of α‐syn accumulations by excess HSP did not eliminate fragmentation. Further, deletion of the C‐terminus (α‐syn1‐120) or the NAC did not affect mitochondrial fragmentation. α‐syn‐mediated mitochondrial fragments were oxidized as assayed by the in vivo oxidation markers mitotimer, mito‐roGFP2‐ORP1 and mito‐roGFP2‐GRX1, which were rescued by deletion of the C‐terminus. While α‐syn‐mediated oxidized mitochondrial fragments showed biased retrograde motility, α‐syn1‐120‐mediated healthy fragments did not. Intriguingly, α‐syn‐mediated fragmentation was rescued by PINK1/PARKIN expression, but not the fragmentation caused by deletion of the C‐terminus. Conclusion Our study demonstrates that under physiological conditions, α‐syn N‐ and C‐terminal regions have distinct functions on mitochondrial fission and oxidation, opening up a previously unknown α‐syn‐mediated mitochondrial defective pathogenic pathway for PD.