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Tau-induced mitochondrial membrane perturbation is dependent upon cardiolipin
- Source :
- Biochimica et biophysica acta. Biomembranes. 1862(2)
- Publication Year :
- 2019
-
Abstract
- Misfolding 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-channel electrophysiology, we could demonstrate the formation of non-selective ion-conducting tau nanopores exhibiting multilevel conductances in mito-mimetic bilayers. Taken together, the data presented here advances a scenario in which toxic cytosolic entities of tau protein would target mitochondrial organelles by associating with their CL-rich membrane domains, leading to membrane poration and compromised mitochondrial structural integrity.
- Subjects :
- 0301 basic medicine
Pore complex
Cardiolipins
Tau protein
Biophysics
tau Proteins
Mitochondrion
Biochemistry
Permeability
03 medical and health sciences
chemistry.chemical_compound
Nanopores
0302 clinical medicine
Organelle
Cardiolipin
Humans
Inner mitochondrial membrane
biology
Chemistry
Cell Biology
Cytosol
030104 developmental biology
Mitochondrial permeability transition pore
Mitochondrial Membranes
biology.protein
Protein Multimerization
030217 neurology & neurosurgery
Protein Binding
Subjects
Details
- ISSN :
- 18792642
- Volume :
- 1862
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta. Biomembranes
- Accession number :
- edsair.doi.dedup.....ef1d3096e3aa4e2b640ddecfe34839ec