Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes

ACS Chem Neurosci. 2019 Aug 21;10(8):3815-3829

Authors/Editors: Stephanie Ghio
Angelique Camilleri
Mario Caruana
Viktoria C Ruf
Felix Schmidt
Andrei Leonov
Sergey Ryazanov
Christian Griesinger
Ruben J Cauchi
Frits Kamp
Armin Giese
Neville Vassallo
Publication Date: 2019
Type of Publication: Journal Article

Aggregation of the amyloid-forming α-synuclein (αS) protein is closely associated with the etiology of Parkinson's disease (PD), the most common motor neurodegenerative disorder. Many studies have shown that soluble aggregation intermediates of αS, termed oligomers, permeabilize a variety of phospholipid membranes; thus, membrane disruption may represent a key pathogenic mechanism of αS toxicity. Given the centrality of mitochondrial dysfunction in PD, we therefore probed the formation of ion-permeable pores by αS oligomers in planar lipid bilayers reflecting the complex phospholipid composition of mitochondrial membranes. Using single-channel electrophysiology, we recorded distinct multilevel conductances (100-400 pS) with stepwise current transitions, typical of protein-bound nanopores, in mitochondrial-like membranes. Crucially, we observed that the presence of cardiolipin (CL), the signature phospholipid of mitochondrial membranes, enhanced αS-lipid interaction and the membrane pore-forming activity of αS oligomers. Further, preincubation of isolated mitochondria with a CL-specific dye protected against αS oligomer-induced mitochondrial swelling and release of cytochrome c. Hence, we favor a scenario in which αS oligomers directly porate a local lipid environment rich in CL, for instance outer mitochondrial contact sites or the inner mitochondrial membrane, to induce mitochondrial dysfunction. Pharmacological modulation of αS pore complex formation might thus preserve mitochondrial membrane integrity and alleviate mitochondrial dysfunction in PD.

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