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

• Published in: Developmental cell Vol. 40; no. 6; pp. 583 - 594.e6
• Main Authors: Bordt, Evan A., Clerc, Pascaline, Roelofs, Brian A., Saladino, Andrew J., Tretter, László, Adam-Vizi, Vera, Cherok, Edward, Khalil, Ahmed, Yadava, Nagendra, Ge, Shealinna X., Francis, T. Chase, Kennedy, Nolan W., Picton, Lora K., Kumar, Tanya, Uppuluri, Sruti, Miller, Alexandrea M., Itoh, Kie, Karbowski, Mariusz, Sesaki, Hiromi, Hill, R. Blake, Polster, Brian M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2017
• Subjects: Animals; bioenergetics; brain; Cell Respiration - drug effects; Chlorocebus aethiops; COS Cells; Dynamins - antagonists & inhibitors; Dynamins - metabolism; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - metabolism; Fibroblasts - metabolism; Fibroblasts - ultrastructure; fission; fragmentation; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - metabolism; Humans; Mice; Mice, Knockout; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - metabolism; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - metabolism; NAD - metabolism; neuron; Neurons - metabolism; Oxidation-Reduction - drug effects; Oxygen Consumption - drug effects; Quinazolinones - pharmacology; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; respiration; reverse electron transfer; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; succinate; superoxide; succinate; bioenergetics; mitochondria; fission; neuron; reverse electron transfer; respiration; superoxide; brain; fragmentation
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.02.020

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. [Display omitted] •mdivi-1 does not impair Drp1 GTPase activity or acutely elongate mitochondria•mdivi-1 reversibly inhibits respiration at mitochondrial complex I•mdivi-1 inhibits reverse electron transfer reactive oxygen species (ROS) production•Effects of mdivi-1 on respiration and ROS are independent of Drp1 Bordt, Clerc et al. show that the putative Drp1 inhibitor mdivi-1 reversibly inhibits mitochondrial complex I without impairing Drp1 GTPase activity or lengthening mitochondria. mdivi-1 attenuates mitochondrial reactive oxygen species production under conditions relevant to ischemia/reperfusion injury. These mechanisms may provide an alternative explanation for some of mdivi-1's in vivo effects.