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A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.
- Source :
-
Journal of cell science [J Cell Sci] 2013 Feb 01; Vol. 126 (Pt 3), pp. 789-802. Date of Electronic Publication: 2012 Dec 13. - Publication Year :
- 2013
-
Abstract
- Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and reactive oxygen species (ROS) production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. Taken together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for the treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur.
- Subjects :
- Apoptosis
Autophagy
Cell Line
Dynamins
Enzyme Inhibitors chemistry
GTP Phosphohydrolases chemistry
GTP Phosphohydrolases genetics
Gene Knockout Techniques
Humans
Membrane Potential, Mitochondrial genetics
Microtubule-Associated Proteins genetics
Mitochondrial Proteins genetics
Molecular Targeted Therapy
Neuroprotective Agents pharmacology
Oxidative Stress
Oxidoreductases metabolism
Parkinson Disease drug therapy
Parkinson Disease genetics
Peptide Fragments chemistry
Plant Proteins metabolism
Reactive Oxygen Species metabolism
Transgenes genetics
Dopaminergic Neurons physiology
Enzyme Inhibitors pharmacology
GTP Phosphohydrolases antagonists & inhibitors
GTP Phosphohydrolases pharmacology
Microtubule-Associated Proteins antagonists & inhibitors
Mitochondria physiology
Mitochondrial Dynamics genetics
Mitochondrial Proteins antagonists & inhibitors
Parkinson Disease enzymology
Peptide Fragments pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9137
- Volume :
- 126
- Issue :
- Pt 3
- Database :
- MEDLINE
- Journal :
- Journal of cell science
- Publication Type :
- Academic Journal
- Accession number :
- 23239023
- Full Text :
- https://doi.org/10.1242/jcs.114439