UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
Web: http://www.um.edu.mt/events/scisem/
Email: scisem@um.edu.mt
Abstract form
Title: The role of cardiolipin in the interaction of amyloidogenic
proteins with mitochondrial membranes
Presenter: Angelique Camilleri
Contact address: Room 127, Faculty of Medicine & Surgery, University of Malta
Tel: 2340 2286
Fax: N/A
Email: angelique.camilleri.03@um.edu.mt
Presentation date: Monday, 9th March 2015
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are
neurodegenerative disorders characterised by the misfolding of proteins into soluble
prefibrillar aggregates, both intracellularly and extracellularly. These include the
amyloid-beta peptide and the microtubule-associated protein Tau in AD, and the αsynuclein protein (α-syn) in PD. Protein aggregate complexes have an intrinsic ability
to interact with and destabilise biological membranes, including those of mitochondrial
organelles. The main aims of this study are, (i) to investigate the molecular mechanism
of the interaction between aggregates of the amyloidogenic proteins α-syn and Tau and
mitochondrial membranes; and (ii) to screen for small-molecule compounds and plant
extracts which can best protect mitochondrial membranes against aggregate insult. As
model systems, we made use of lipid vesicles with defined membrane compositions
that mimic those of mitochondrial membranes, and of respiring mitochondria isolated
from neuronal SH-SY5Y cells. We found that low micromolar concentrations of α-syn
aggregates and Tau protein efficiently induced mitochondrial swelling, and also
triggered cytochrome c release (CCR). Furthermore, it was shown that mitochondrial
membrane depolarisation was not involved in the mitochondrial toxicity of α-syn. In
keeping with this finding, none of various pharmacological inhibitors of the
mitochondrial permeability transition pore that were tested, had any significant effect
on swelling or CCR. Interestingly, however, the cardiolipin (CL)-binding dye 10-N-nonyl
acridine orange robustly protected mitochondria from both swelling and CCR, induced
by α-syn and Tau aggregates. Using a gel-binding retardation assay, it was confirmed
that indeed Tau has a high affinity for mitochondrial-like membranes containing CL.
Taken together, our results point to a critical role for CL, a unique phospholipid
enriched in mitochondrial membranes, in the interaction with, and permeabilisation of,
mitochondrial membranes by α-syn and Tau.