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The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species.
Bordt, Evan A; Clerc, Pascaline; Roelofs, Brian A; Saladino, Andrew J; Tretter, László; Adam-Vizi, Vera; Cherok, Edward; Khalil, Ahmed; Yadava, Nagendra; Ge, Shealinna X; Francis, T Chase; Kennedy, Nolan W; Picton, Lora K; Kumar, Tanya; Uppuluri, Sruti; Miller, Alexandrea M; Itoh, Kie; Karbowski, Mariusz; Sesaki, Hiromi; Hill, R Blake; Polster, Brian M.
Afiliación
  • Bordt EA; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Clerc P; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Roelofs BA; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Saladino AJ; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
  • Tretter L; MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
  • Adam-Vizi V; MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
  • Cherok E; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Khalil A; Pioneer Valley Life Sciences Institute, Springfield, MA 01109, USA; Baystate Medical Center, Springfield, MA 01109, USA.
  • Yadava N; Pioneer Valley Life Sciences Institute, Springfield, MA 01109, USA; Baystate Medical Center, Springfield, MA 01109, USA; Department of Biology, University of Massachusetts, Amherst, MA 01003, USA.
  • Ge SX; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Francis TC; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Kennedy NW; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Picton LK; Department of Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Kumar T; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Uppuluri S; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Miller AM; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Itoh K; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Karbowski M; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Sesaki H; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Hill RB; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Polster BM; Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: bpolster@anes.umm.edu.
Dev Cell ; 40(6): 583-594.e6, 2017 03 27.
Article en En | MEDLINE | ID: mdl-28350990
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 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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Proteínas Mitocondriales / Dinaminas / Complejo I de Transporte de Electrón / Quinazolinonas / GTP Fosfohidrolasas / Proteínas Asociadas a Microtúbulos / Mitocondrias Límite: Animals / Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Proteínas Mitocondriales / Dinaminas / Complejo I de Transporte de Electrón / Quinazolinonas / GTP Fosfohidrolasas / Proteínas Asociadas a Microtúbulos / Mitocondrias Límite: Animals / Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos