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In this study, we tracked the intracellular conformational states of \u03b1-Syn using a single-molecule F\u00f6rster resonance energy transfer (smFRET) biosensor, and we show here that \u03b1-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T \u03b1-Syn, and cardiolipin is sequestered within aggregating lipid\u2013protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T \u03b1-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)\u2013derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo \u03b1-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.<\/jats:p>","DOI":"10.1038\/s41593-022-01140-3","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T12:07:04Z","timestamp":1661861224000},"page":"1134-1148","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":277,"title":["Pathological structural conversion of \u03b1-synuclein at the mitochondria induces neuronal toxicity"],"prefix":"10.1038","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9414-8214","authenticated-orcid":false,"given":"Minee 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