title: The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species.
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 O2consumption 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.
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Bordt
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Clerc
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Roelofs
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saladino
authors.affiliation: MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tretter
authors.affiliation: MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
authors.forename: Vera
authors.initials: V
authors.lastname: Adam-Vizi
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Cherok
authors.affiliation: Pioneer Valley Life Sciences Institute, Springfield, MA 01109, USA; Baystate Medical Center, Springfield, MA 01109, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khalil
authors.affiliation: 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.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Yadava
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Shealinna X
authors.initials: SX
authors.lastname: Ge
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: T Chase
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Nolan W
authors.initials: NW
authors.lastname: Kennedy
authors.affiliation: Department of Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Picton
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Kumar
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Uppuluri
authors.affiliation: Department of Anesthesiology, The Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Alexandrea M
authors.initials: AM
authors.lastname: Miller
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kie
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: R Blake
authors.initials: RB
authors.lastname: Hill
authors.affiliation: 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.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Polster
mesh_terms: D000818:Animals; D019556:COS Cells; D019069:Cell Respiration / Q000187:drug effects; D002522:Chlorocebus aethiops; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D052999:Quinazolinones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C493237:Ndi1 protein, S cerevisiae; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D009243:NAD; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins; D042967:Electron Transport Complex I
keywords: bioenergetics; brain; fission; fragmentation; mitochondria; neuron; respiration; reverse electron transfer; succinate; superoxide