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

Evan A. Bordt, Pascaline Clerc, Brian A. Roelofs, Andrew J. Saladino, L. Tretter, V. Ádám-Vizi, Edward Cherok, Ahmed Khalil, Nagendra Yadava, Shealinna X. Ge, T. Chase Francis, Nolan W. Kennedy, Lora K. Picton, Tanya Kumar, Sruti Uppuluri, Alexandrea M. Miller, Kie Itoh, Mariusz Karbowski, Hiromi Sesaki, R. Blake HillBrian M. Polster

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Mitochondrial fission mediated by the GTPase dynamin-related protein 1 (Drp1) is an attractive drug target in numerous maladies that range from heart disease to neurodegenerative disorders. The compound mdivi-1 is widely reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate brain injury. Here, we show that mdivi-1 reversibly inhibits mitochondrial complex I-dependent O2 consumption and reverse electron transfer-mediated reactive oxygen species (ROS) production at concentrations (e.g., 50 μM) used to target mitochondrial fission. Respiratory inhibition is rescued by bypassing complex I using yeast NADH dehydrogenase Ndi1. Unexpectedly, respiratory impairment by mdivi-1 occurs without mitochondrial elongation, is not mimicked by Drp1 deletion, and is observed in Drp1-deficient fibroblasts. In addition, mdivi-1 poorly inhibits recombinant Drp1 GTPase activity (Ki > 1.2 mM). Overall, these results suggest that mdivi-1 is not a specific Drp1 inhibitor. The ability of mdivi-1 to reversibly inhibit complex I and modify mitochondrial ROS production may contribute to effects observed in disease models.

Original languageEnglish
Pages (from-to)583-594.e6
JournalDevelopmental Cell
Volume40
Issue number6
DOIs
Publication statusPublished - Mar 27 2017

Keywords

  • bioenergetics
  • brain
  • fission
  • fragmentation
  • mitochondria
  • neuron
  • respiration
  • reverse electron transfer
  • succinate
  • superoxide

ASJC Scopus subject areas

  • Developmental Biology

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  • Cite this

    Bordt, E. A., Clerc, P., Roelofs, B. A., Saladino, A. J., Tretter, L., Ádám-Vizi, V., Cherok, E., Khalil, A., Yadava, N., Ge, S. X., Francis, T. C., Kennedy, N. W., Picton, L. K., Kumar, T., Uppuluri, S., Miller, A. M., Itoh, K., Karbowski, M., Sesaki, H., ... Polster, B. M. (2017). The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species. Developmental Cell, 40(6), 583-594.e6. https://doi.org/10.1016/j.devcel.2017.02.020