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The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen

Evan A Bordt1, Pascaline Clerc1, Brian A Roelofs1

  • 1Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Developmental Cell
|March 29, 2017
PubMed

Insights

Mdivi-1, a compound targeting mitochondrial fission, actually inhibits mitochondrial complex I respiration and reactive oxygen species production, not dynamin-related protein 1 (Drp1) as previously thought.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • Mitochondrial fission, regulated by dynamin-related protein 1 (Drp1), is a key process in cellular health and disease.
  • The compound mdivi-1 is widely used as an inhibitor of Drp1-dependent mitochondrial fission.
  • Mdivi-1 has been reported to elongate mitochondria and offer protection in various disease models.

Purpose of the Study:

  • To investigate the precise mechanism of action of mdivi-1.
  • To determine if mdivi-1 specifically inhibits Drp1 GTPase activity and mitochondrial fission.
  • To elucidate the effects of mdivi-1 on mitochondrial respiration and reactive oxygen species (ROS) production.

Main Methods:

  • Assessed mitochondrial oxygen consumption and ROS production in the presence of mdivi-1.
  • Utilized yeast NADH dehydrogenase (Ndi1) to bypass complex I and rescue respiratory inhibition.
  • Examined the effects of mdivi-1 on Drp1-deficient cells and recombinant Drp1 GTPase activity.

Main Results:

  • Mdivi-1 reversibly inhibits mitochondrial complex I-dependent oxygen consumption at concentrations used for targeting fission.
  • Mdivi-1 alters mitochondrial ROS production via reverse electron transfer.
  • Respiratory inhibition by mdivi-1 occurs independently of mitochondrial elongation and Drp1 activity.
  • Mdivi-1 exhibits weak inhibition of recombinant Drp1 GTPase activity.

Conclusions:

  • Mdivi-1 is not a specific inhibitor of Drp1-dependent mitochondrial fission.
  • Mdivi-1's primary action involves the reversible inhibition of mitochondrial complex I.
  • The compound's effects on complex I and ROS production may explain its observed therapeutic effects in disease models.
Keywords:
bioenergeticsbrainfissionfragmentationmitochondrianeuronrespirationreverse electron transfersuccinatesuperoxide

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