Please use this identifier to cite or link to this item: https://www.um.edu.mt/library/oar/handle/123456789/88368
Title: Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes
Authors: Ghio, Stephanie
Camilleri, Angelique
Caruana Grech Perry, Mario
Ruf, Viktoria C.
Schmidt, Felix
Leonov, Andrei
Ryazanov, Sergey
Griesinger, Christian
Cauchi, Ruben J.
Kamp, Frits
Giese, Armin
Vassallo, Neville
Keywords: Cardiolipin
Electrophysiology
Mitochondrial membranes
Oligomers -- Analysis
Synucleins
Issue Date: 2019
Publisher: American Chemical Society
Citation: Ghio, S., Camilleri, A., Caruana, M., Ruf, V.C., Schmidt, F., Leonov, A.,…Vassallo, N. (2019). Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes. ACS Chemical Neuroscience, 10, 3815-3829.
Abstract: 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 mitochondriallike 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 oligomerinduced 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.
URI: https://www.um.edu.mt/library/oar/handle/123456789/88368
Appears in Collections:Scholarly Works - FacM&SPB

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