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

Abstract

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 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, 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.

Sepia Ink Oligopeptide Induces Apoptosis of Lung Cancer Cells via Mitochondrial Pathway

“…2A, B). To further validate the crucial role of mitochondrial apoptosis in CSIO-elicited cell death, here we employed mdivi-1, a selective inhibitor of mitochondrial fission protein, to specifically block mitochondria mediated cell apoptosis [13] without influencing other apoptotic cues. We preliminarily evaluated the potential impact on mitochondrial dynamics via interrogation of relevant gene expressions.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Whether this pro-apoptotic role of mdivi-1 in regulating MOMP opening, and subsequent cytC release, is completely dependent on its inhibitory effect on Dpr1 or to its possible off-targets (such as MOMP assembly itself [166]) is currently not clarified. Indeed, in a few models, such as neuronal and MEF cell lines, mdivi-1 impinges on ROS levels and ETC complex I without affecting mitochondrial length or Drp1 [167]. Moreover, given the detrimental effect of prolonged alterations in mitochondrial morphology, the possibility to modulate locally and in a definite temporal window mitochondrial fission through mdivi-1 treatment could become a potential promising therapeutical anti-cancer treatment, although some concerns about its in vivo cytotoxicity must be previously resolved (see [160] for a review).…”

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

“…Objective parameterization of mitochondrial shapes requires sophisticated image analysis methods and software (Giedt et al, 2016; McClatchey et al, 2016; Vinegoni et al, 2016). These morphological quantifications are useful experimental readouts, but it is important to appreciate that morphology is not a unique determinant of the underlying dynamical phenomena (Bordt et al, 2017). For example, elongated mitochondrial shape could arise from increased fusion, decreased fission, increased growth or any combination of these phenomena.…”

“…Drp1 inhibitors are being developed as potential therapeutics to suppress neurodegeneration. However, the fission inhibitor mdivi-1, originally identified as a direct inhibitor of Drp1, instead appears to be an inhibitor of Complex I of the mitochondrial respiratory chain (Bordt et al, 2017). …”