[PDF][PDF] The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species

EA Bordt, P Clerc, BA Roelofs, AJ Saladino, L Tretter… - Developmental cell, 2017 - cell.com
EA Bordt, P Clerc, BA Roelofs, AJ Saladino, L Tretter, V Adam-Vizi, E Cherok, A Khalil
Developmental cell, 2017cell.com
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 O 2 consumption and reverse
electron transfer-mediated reactive oxygen species (ROS) production at concentrations (eg …
Summary
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.
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