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The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species. Dev Cell 2017 03 27;40(6):583-594.e6

Date

03/30/2017

Pubmed ID

28350990

Pubmed Central ID

PMC5398851

DOI

10.1016/j.devcel.2017.02.020

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 O 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 (K > 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 BM

Author

Ronald Blake Hill PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
COS Cells
Cell Respiration
Cercopithecus aethiops
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
jenkins-FCD Prod-399 190a069c593fb5498b7fcd942f44b7bc9cdc7ea1