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

2017; Elsevier BV; Volume: 40; Issue: 6 Linguagem: Inglês

10.1016/j.devcel.2017.02.020

1878-1551

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

Cancer, Hypoxia, and Metabolism

Highlights•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 Drp1SummaryMitochondrial 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.Graphical abstract