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Dev Cell. 2017 Mar 27;40(6):583-594.e6. doi: 10.1016/j.devcel.2017.02.020.

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species.

Author information

1
Department of Anesthesiology, 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; Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
3
MTA-SE Laboratory for Neurobiochemistry, Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
4
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
5
Pioneer Valley Life Sciences Institute, Springfield, MA 01109, USA; Baystate Medical Center, Springfield, MA 01109, USA.
6
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.
7
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
8
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
9
Department of Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
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.

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.

KEYWORDS:

bioenergetics; brain; fission; fragmentation; mitochondria; neuron; respiration; reverse electron transfer; succinate; superoxide

PMID:
28350990
PMCID:
PMC5398851
DOI:
10.1016/j.devcel.2017.02.020
[Indexed for MEDLINE]
Free PMC Article

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