Tau-induced mitochondrial membrane perturbation is dependent upon cardiolipin

Publication date: Available online 12 September 2019Source: Biochimica et Biophysica Acta (BBA) - BiomembranesAuthor(s): Angelique Camilleri, Stephanie Ghio, Mario Caruana, Daniel Weckbecker, Felix Schmidt, Frits Kamp, Andrei Leonov, Sergey Ryazanov, Christian Griesinger, Armin Giese, Ruben J. Cauchi, Neville VassalloAbstractMisfolding and aggregate formation by the tau protein has been closely related with neurotoxicity in a large group of human neurodegenerative disorders, which includes Alzheimer's disease. Here, we investigate the membrane-active properties of tau oligomers on mitochondrial membranes, using minimalist in vitro model systems. Thus, exposure of isolated mitochondria to oligomeric tau evoked a disruption of mitochondrial membrane integrity, as evidenced by a combination of organelle swelling, efflux of cytochrome c and loss of the mitochondrial membrane potential. Tau-induced mitochondrial dysfunction occurred independently of the mitochondrial permeability transition (mPT) pore complex. Notably, mitochondria were rescued by pre-incubation with 10-N-nonyl acridine orange (NAO), a molecule that specifically binds cardiolipin (CL), the signature phospholipid of mitochondrial membranes. Additionally, NAO prevented direct binding of tau oligomers to isolated mitochondria. At the same time, tau proteins exhibited high affinity to CL-enriched membranes, whilst permeabilisation of lipid vesicles also strongly correlated with CL content. Intriguingly, using single-c...
Source: Biochimica et Biophysica Acta (BBA) Biomembranes - Category: Biochemistry Source Type: research