Blindheim 2018 IOC134
|Bioactive lipophilic substances and their effect on neuronal cells.|
Link: Mitochondr Physiol Network 23.08
Neurodegenerative diseases, including Alzheimer´s Disease (AD) and Parkinson´s Disease (PD), lack efficient medications to modify pathogenetic mechanisms. Affecting millions of people worldwide every year, the need for disease-modifying therapies is pressing.
There is strong evidence for mitochondrial dysfunction playing a critical role in the development of AD and PD, implicated by the accumulation of amyloid-β and α-synuclein respectively. Synaptic failure and neuronal death are also consequences of impaired mitochondrial biogenesis, bioenergetics and transport [1,2].
Studies have shown that synthetic heteroatom-substituted fatty acids in β-position such as tetradecylthioacetic acid (TTA) have favorable effects on mitochondrial function. This includes stimulation of mitochondrial and peroxisomal fatty acid oxidation , antioxidant capacity and mild uncoupling by UCP2 and UCP3. Induction of mitochondrial biogenesis and respiration by TTA have the potential to repopulate neurites with mitochondria, possibly preventing neurodegeneration, synaptic failure and neuronal death.
During the work with my master´s thesis, I wish to investigate the effects of TTA along with other novel modified fatty acids on neuronal cells. These include triple-TTA with a triple bond at the methyl end, possibly slowing the catabolism, and N-TTA which has a nitrogen atom in β-position instead of sulphur.
Starting procedures have included viability tests on the cell lines used in the project, and determination of cell toxicity of the fatty acids using WST-1-assay and spectrophotometric detection. When appropriate concentrations of the fatty acids are known, the plan is to perform in vitro respiration assays to determine mitochondrial activity in the cell lines after treatment with the selected compounds. Oxygen utilization in response to the treatment will be quantified by polarographic respirometry (OROBOROS® Oxygraph), after permeabilization of the cells. By employing various metabolic substrates and molecular manipulators we can differentiate functional and regulatory aspects of single components of the respiratory chain. Specifically, we will examine if the fatty acids alter the capacity or coupling state of the mitochondria.
Labels: MiParea: Respiration Pathology: Alzheimer's, Parkinson's
Tissue;cell: Nervous system Preparation: Permeabilized cells
Regulation: Fatty acid
Blindheim DF(1), Giil LM(1,2), Tzoulis C(1), Berge RK(1), Bjoerndal B(1)
- Dept Clinical Science, Univ Bergen
- Haraldsplass Deaconess Hospital; Bergen, Norway
- Cabezas-Opazo FA, Vergara-Pulgar K, Perez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA (2015) Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev. 2015:509654.
- Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson's disease. J Neurochem. 1:216-31.
- Berge RK, Skorve J, Tronstad KJ, Berge K, Gudbrandsen OA, Grav H (2002) Metabolic effects of thia fatty acids. Curr Opin Lipidol. 13:295-304.