Corona 2014 Exp Neurol
|Corona JC, de Souza SC, Duchen MR (2014) PPARγ activation rescues mitochondrial function from inhibition of 2 complex I and loss of PINK1. Exp Neurol 253:16-27.|
Abstract: Parkinson's disease has long been associated with impaired mitochondrial complex I activity, while several gene defects associated with familial Parkinson's involve defects in mitochondrial function or 'quality control' pathways, causing an imbalance between mitochondrial biogenesis and removal of dysfunctional mitochondria by autophagy. Amongst these are mutations of the gene for PTEN-induced kinase 1 (PINK1) in which mitochondrial function is abnormal. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor and ligand-dependent transcription factor, regulates pathways of inflammation, lipid and carbohydrate metabolism, antioxidant defences and mitochondrial biogenesis. We have found that inhibition of complex I in human differentiated SHSY-5Y cells by the complex I inhibitor rotenone irreversibly decrease mitochondrial mass, membrane potential and oxygen consumption, while increasing free radical generation and autophagy. Similar changes are seen in PINK1 knockdown cells, in which potential, oxygen consumption and mitochondrial mass are all decreased. In both models, all these changes were reversed by pre-treatment of the cells with the PPARγ agonist, rosiglitazone, which increased mitochondrial biogenesis, increased oxygen consumption and suppressed free radical generation and autophagy. Thus, rosiglitazone is neuroprotective in two different models of mitochondrial dysfunction associated with Parkinson's disease through a direct impact on mitochondrial function.
• Keywords: 1-Methyl-4-phenylpyridinium ion, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, 3, 3′- dihexyloxacarbocyanine iodide, Autophagy, CI, COX-1, Cell death, DHE, DiOC(6)(3), Dihydroethidium, MPP(+), MPTP, Mitochondrial biogenesis, Mitochondrial membrane potential, NAD(P)H:quinone oxidoreductase 1, NQO1, Nrf2, Oxidative stress, PD, PGC1, PI, PINK1, PPARγ, PTEN-induced putative kinase 1, Parkinson's disease, RGS, ROS, Rosiglitazone, Rotenone, SDHA, SOD1, TMRM, TZDs, Tetramethylrhodamine methyl ester, Complex I, Mitochondrial transcription factor A, mtTFA, Nuclear factor (erythroid-derived 2)-like 2, Peroxisome proliferator-activated receptor gamma, Peroxisome proliferator-activated receptor gamma coactivator 1, Propidium Iodide, Reactive oxygen species, Subunit I of complex IV, Subunit of Complex II, Superoxide dismutase 1, Thiazolidinediones
• O2k-Network Lab: UK London Duchen MR
Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression Pathology: Parkinson's
Organism: Human Tissue;cell: Neuroblastoma Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET