PUBLICATION
Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells
- Authors
- Pinho, B.R., Reis, S.D., Hartley, R.C., Murphy, M.P., Oliveira, J.M.A.
- ID
- ZDB-PUB-181106-4
- Date
- 2018
- Source
- Free radical biology & medicine 130: 318-327 (Journal)
- Registered Authors
- Keywords
- Huntington's disease, MitoParaquat, Mitochondria, Parkinson's disease, Superoxide, Zebrafish
- MeSH Terms
-
- Animals
- Antioxidants/pharmacology
- Brain/drug effects
- Brain/metabolism
- Brain/pathology
- Humans
- Huntingtin Protein/genetics*
- Huntington Disease/drug therapy*
- Huntington Disease/genetics
- Huntington Disease/pathology
- Mitochondria/drug effects
- Mitochondria/metabolism
- Oxidation-Reduction/drug effects
- Oxidative Stress/drug effects*
- Paraquat/pharmacology
- Parkinson Disease/drug therapy*
- Parkinson Disease/genetics
- Parkinson Disease/metabolism
- Parkinson Disease/pathology
- Phenotype
- Protein Aggregation, Pathological/drug therapy*
- Protein Aggregation, Pathological/genetics
- Protein Aggregation, Pathological/pathology
- Reactive Oxygen Species/metabolism
- Rotenone/pharmacology
- Superoxides/metabolism
- Tyrosine 3-Monooxygenase/genetics
- Zebrafish
- PubMed
- 30389496 Full text @ Free Radic. Biol. Med.
Citation
Pinho, B.R., Reis, S.D., Hartley, R.C., Murphy, M.P., Oliveira, J.M.A. (2018) Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells. Free radical biology & medicine. 130:318-327.
Abstract
Superoxide generation by mitochondria respiratory complexes is a major source of reactive oxygen species (ROS) which are capable of initiating redox signalling 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping