A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity

J Cell Sci. 2013 Feb 1;126(Pt 3):789-802. doi: 10.1242/jcs.114439. Epub 2012 Dec 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Autophagy
  • Cell Line
  • Dopaminergic Neurons / physiology*
  • Dynamins
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • GTP Phosphohydrolases / antagonists & inhibitors*
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / pharmacology*
  • Gene Knockout Techniques
  • Humans
  • Membrane Potential, Mitochondrial / genetics
  • Microtubule-Associated Proteins / antagonists & inhibitors*
  • Microtubule-Associated Proteins / genetics
  • Mitochondria / physiology*
  • Mitochondrial Dynamics* / genetics
  • Mitochondrial Proteins / antagonists & inhibitors*
  • Mitochondrial Proteins / genetics
  • Molecular Targeted Therapy
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress
  • Oxidoreductases / metabolism
  • Parkinson Disease / drug therapy
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Plant Proteins / metabolism
  • Reactive Oxygen Species / metabolism
  • Transgenes / genetics

Substances

  • Enzyme Inhibitors
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Neuroprotective Agents
  • P110 peptide
  • Peptide Fragments
  • Plant Proteins
  • Reactive Oxygen Species
  • Oxidoreductases
  • flavonol synthase
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dynamins