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

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          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 O 2 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 i>1.2 mM). Overall, 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.

          eTOC

          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.

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          Author and article information

          Journal
          101120028
          22411
          Dev Cell
          Dev. Cell
          Developmental cell
          1534-5807
          1878-1551
          17 March 2017
          27 March 2017
          27 March 2018
          : 40
          : 6
          : 583-594.e6
          Affiliations
          [1 ]Department of Anesthesiology and the Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
          [2 ]Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
          [3 ]Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
          [4 ]Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
          [5 ]Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Baltimore, MD 21201, USA
          [6 ]MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary
          [7 ]Pioneer Valley Life Sciences Institute, Springfield, MA 01109, USA
          [8 ]Baystate Medical Center, Springfield, MA 01109, USA
          [9 ]Department of Biology, University of Massachusetts, Amherst, Massachusetts 01003, USA
          [10 ]Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
          [11 ]Department of Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [12 ]Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          Author notes
          [* ]Correspondence and Lead Contact: bpolster@ 123456anes.umm.edu
          [#]

          These authors contributed equally to this work

          Article
          PMC5398851 PMC5398851 5398851 nihpa856773
          10.1016/j.devcel.2017.02.020
          5398851
          28350990
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          Article

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