Differential interaction of α-synuclein N-terminal segment with mitochondrial model membranes

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

“…42,43 Compelling evidence has emerged from human dopaminergic neuronal cultures and post-mortem PD brains that αS directly interacts with mitochondria, with potentially deleterious consequences. 44,45 However, the exact molecular mechanisms of αS-induced mitochondrial dysfunction are still unclear. Therefore, given the centrality of mitochondrial dysfunction in PD pathogenesis, 46 in the present study we sought to uncover whether αS oligomers are able to permeabilize mitochondria membranes through ion-conducting pore formation and address whether this is connected to the presence of CL in the membrane.…”

“…Mitochondrial bioenergetic efficiency is dependent upon CL, since CL molecules stabilize supramolecular structures assembled from respiratory chain complexes in the IMM, thereby enhancing the facility of electron transfer and maximizing oxidative phosphorylation. , In point of fact, a decline in mitochondrial CL content was associated with bioenergetic deficits in mitochondria of neurons from α-synuclein knockout mice . It has been suggested that CL might help target oligomeric aggregates of αS intracellularly to mitochondria and mediate disruption of mitochondrial membranes. , Mitochondrial imported αS is predominantly associated with the CL-IMM, with the N-terminal segment of αS being essential for its anchoring to mitochondria. , Compelling evidence has emerged from human dopaminergic neuronal cultures and post-mortem PD brains that αS directly interacts with mitochondria, with potentially deleterious consequences. , However, the exact molecular mechanisms of αS-induced mitochondrial dysfunction are still unclear.…”