The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species. Dev Cell 2017 Mar 27;40(6):583-594.e6
Date
03/30/2017Pubmed ID
28350990Pubmed Central ID
PMC5398851DOI
10.1016/j.devcel.2017.02.020Scopus ID
2-s2.0-85016487669 (requires institutional sign-in at Scopus site) 443 CitationsAbstract
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.
Author List
Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Ge SX, Francis TC, Kennedy NW, Picton LK, Kumar T, Uppuluri S, Miller AM, Itoh K, Karbowski M, Sesaki H, Hill RB, Polster BMMESH terms used to index this publication - Major topics in bold
AnimalsCOS Cells
Cell Respiration
Dynamins
Electron Transport Complex I
Fibroblasts
GTP Phosphohydrolases
Humans
Mice
Mice, Knockout
Microtubule-Associated Proteins
Mitochondria
Mitochondrial Proteins
NAD
Neurons
Oxidation-Reduction
Oxygen Consumption
Quinazolinones
Rats, Sprague-Dawley
Reactive Oxygen Species
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
