Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols

Abstract

Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterised by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, and (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Aβ42 peptide), wild-type α-synuclein (α-syn), mutant α-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial-like vesicles, and triggered cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Aβ42, α-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases.

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

“…2 (continued) L.A. Esposito and amyloidogenic peptides may derive, in part, through presentation of at least one face of multiple phenolic groups in a planar orientation that interrupts amyloid intermolecular hydrogen bonding. These results are consistent with a recent report that polyphenols, including black tea, lessened the effects of exogenous α-synuclein on mitochondrial function [256].…”

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

“…The acceleration of cytochrome c release in ␣Syn-treated mitochondria was likewise rescued by preincubation with CsA. This result suggests that cytochrome c release was also regulated by the mPTP in our system rather than by channels formed via direct permeabilization of the outer membrane by oligomeric ␣Syn, as has been suggested (75). Although the role of mitochondrial permeability transition in PD-related cell death requires further study, two recent reports support the in vivo relevance of our data.…”

P1‐109: Mitochondrial Dysfunction Induced by a Posttranslationally Modified Amyloid Linked to a Familial Mutation in an Alternative Model of Neurodegeneration

“…Similarly, in cells challenged with Bri1-23 pE or Bri1-23 E, cyt c remained confined to the mitochondria as in the control cells. Cells challenged with Aβ42 exhibited cyt c release at all time-points studied, in agreement with previous reports [60][61][62].…”