Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide generation by mitochondria respiratory complexes is a major source of reactive oxygen species (ROS) which are capable of initiating redox signaling and oxidative damage. Current understanding of the role of mitochondrial ROS in health and disease has been limited by the lack of experimental strategies to selectively induce mitochondrial superoxide production. The recently-developed mitochondria-targeted redox cycler MitoParaquat (MitoPQ) overcomes this limitation, and has proven effective in vitro and in Drosophila. Here we present an in vivo study of MitoPQ in the vertebrate zebrafish model in the context of Parkinson's disease (PD), and in a human cell model of Huntington's disease (HD). We show that MitoPQ is 100-fold more potent than non-targeted paraquat in both cells and in zebrafish in vivo. Treatment with MitoPQ induced a parkinsonian phenotype in zebrafish larvae, with decreased sensorimotor reflexes, spontaneous movement and brain tyrosine hydroxylase (TH) levels, without detectable effects on heart rate or atrioventricular coordination. Motor phenotypes and TH levels were partly rescued with antioxidant or monoaminergic potentiation strategies. In a HD cell model, MitoPQ promoted mutant huntingtin aggregation without increasing cell death, contrasting with the complex I inhibitor rotenone that increased death in cells expressing either wild-type or mutant huntingtin. These results show that MitoPQ is a valuable tool for cellular and in vivo studies of the role of mitochondrial superoxide generation in redox biology, and as a trigger or co-stressor to model metabolic and neurodegenerative disease phenotypes.
 ...
PMID:Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells. 3038 96

Mechanisms mediating protective effects of dietary restriction during aging are of great interest since activating such mechanisms protect against a wide range of age-related diseases. In mammals key metabolic responses to nutritional deprivation are mediated by the transcription factor PPAR-alpha, which is activated by free fatty acids and promotes lipid metabolism while inhibiting glucose metabolism. The C. elegans gene nhr-49 appears to function similarly in C. elegans. Here we report that protective effects of dietary restriction and inhibition of glucose metabolism to increase lifespan wild-type C. elegans and reduce toxicity in a polyQ model of Huntington's disease in C. elegans are dependent on NHR-49 and its co-activator CREB-Binding Protein (CBP). We have previously demonstrated that inhibition of cbp blocks protective effects of dietary restriction and blocks the molecular switch from glucose metabolism to alternative substrates. Conversely, increased glucose concentration and inhibition of cbp reduce lifespan and increase proteotoxicity. Lactate and inhibition of ETC complex II mimicked toxic effects of glucose on proteotoxicity whereas pyruvate and inhibition of ETC complex I protected against glucose-enhanced proteotoxicity. These results support that PPAR-alpha-like activity mediates protective effects of dietary restriction by reducing glucose metabolism via reducing production of NADH, and corroborate and extend recent studies demonstrating that PPPAR-alpha agonists increase lifespan in C. elegans dependent on NHR-49.
 ...
PMID:Dietary Restriction and Glycolytic Inhibition Reduce Proteotoxicity and Extend Lifespan via NHR-49. 3082 Jan 35


<< Previous 1 2 3 4 5