title: A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.
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.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Case Western Reserve University School of Medicine Cleveland, OH 44106 Cleveland, OH 44106 USA. xxq38@case.edu
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.forename: Nir
authors.initials: N
authors.lastname: Qvit
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Su
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000502:physiology*; D034281:Dynamins; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008928:Mitochondria / Q000502:physiology*; D063154:Mitochondrial Dynamics / Q000235:genetics; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010940:Plant Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; C583855:P110 peptide; D010446:Peptide Fragments; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; C085313:flavonol synthase; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins