Discovery and characterization of selective small molecule inhibitors of the mammalian mitochondrial division dynamin, DRP1

Biochem Biophys Res Commun. 2018 May 15;499(3):556-562. doi: 10.1016/j.bbrc.2018.03.189. Epub 2018 Apr 4.


Balanced rates of mitochondrial division and fusion are required to maintain mitochondrial function, as well as cellular and organismal homeostasis. In mammals, the cellular machines that mediate these processes are dynamin-related GTPases; the cytosolic DRP1 mediates division, while the outer membrane MFN1/2 and inner membrane OPA1 mediate fusion. Unbalanced mitochondrial dynamics are linked to varied pathologies, including cell death and neurodegeneration, raising the possibility that small molecules that target the division and fusion machines to restore balance may have therapeutic potential. Here we describe the discovery of novel small molecules that directly and selectively inhibit assembly-stimulated GTPase activity of the division dynamin, DRP1. In addition, these small molecules restore wild type mtDNA copy number in MFN1 knockout mouse embryonic fibroblast cells, a phenotype linked to deficient mitochondrial fusion activity. Thus, these compounds are unique tools to explore the roles of mitochondrial division in cells, and to assess the potential therapeutic efficacy of rebalancing mitochondrial dynamics in pathologies associated with excessive mitochondrial division.

Keywords: DRP1; Dynamics; Fission; Mitochondria; Small molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Mitochondrial / genetics
  • Drug Discovery*
  • Dynamins / antagonists & inhibitors*
  • Dynamins / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Hydrolysis
  • Mammals / metabolism*
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Guanosine Triphosphate
  • Dynamins