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This study explored the potential of SS\u201031 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating \u03b1\u2010synuclein interaction with the lipid membranes and mitigating the impairment of mitochondrial function induced by \u03b1\u2010synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS\u201031 displaces both wild\u2010type and N\u2010terminal acetylated \u03b1\u2010synuclein from negatively charged small unilamellar vesicles in a dose\u2010dependent manner. Thioflavin\u2010T assay and transmission electron microscopy showed that SS\u201031 inhibits membrane\u2010induced \u03b1\u2010synuclein aggregation and alters the morphology of \u03b1\u2010synuclein fibrils. Moreover, MTT assay and Seahorse Mito Stress Test indicated that SS\u201031 enhances cell viability and restores impaired mitochondrial function in \u03b1\u2010synuclein oligomer\u2010treated neuroblastoma cells. Finally, confocal imaging revealed that SS\u201031 hinders cellular uptake of \u03b1\u2010synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings suggest that SS\u201031 potentially attenuates \u03b1\u2010synuclein induced mitochondrial impairment via its interaction with the lipid membranes, justifying further development of a peptide\u2010based intervention against \u03b1\u2010synuclein mediated pathology.<\/jats:p>","DOI":"10.1111\/cbdd.70332","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:33:51Z","timestamp":1780292031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Peptide\n                    <scp>SS<\/scp>\n                    \u201031 Modulates Membrane Binding and Aggregation of \u03b1\u2010Synuclein and Restores Impaired Mitochondrial Function"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7127-4514","authenticated-orcid":false,"given":"Ewelina","family":"Stefaniak","sequence":"first","affiliation":[{"name":"National Heart and Lung 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