Mitochondrial fission – a drug target for cytoprotection or cytodestruction?

Abstract

Mitochondria are morphologically dynamic organelles constantly undergoing processes of fission and fusion that maintain integrity and bioenergetics of the organelle: these processes are vital for cell survival. Disruption in the balance of mitochondrial fusion and fission is thought to play a role in several pathological conditions including ischemic heart disease. Proteins involved in regulating the processes of mitochondrial fusion and fission are therefore potential targets for pharmacological therapies. Mdivi‐1 is a small molecule inhibitor of the mitochondrial fission protein Drp1. Inhibiting mitochondrial fission with Mdivi‐1 has proven cytoprotective benefits in several cell types involved in a wide array of cardiovascular injury models. On the other hand, Mdivi‐1 can also exert antiproliferative and cytotoxic effects, particularly in hyperproliferative cells. In this review, we discuss these divergent effects of Mdivi‐1 on cell survival, as well as the potential and limitations of Mdivi‐1 as a therapeutic agent.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…However, the complex regulation of mitochondrial dynamics provides many therapeutic targets for the treatment of cerebral ischemia, traumatic brain injury and other neurological disorders. Drp1 has been put forward as a drug target for preventing mitochondrial fragmentation under diverse pathological conditions (Rosdah et al, 2016). Indeed, currently available Drp1 inhibitors have shown neuroprotective properties in animal models of HD (Guo et al, 2013b), PD (Hatch et al, 2014;Filichia et al, 2016) and ischemic stroke (Grohm et al, 2012;Li et al, 2015;Zhang et al, 2013).…”

“…However, a number of surprising observations question the interpretation that inhibition of Drp1 protects neurons from ischemic death by preventing mitochondrial fission. First, mdivi-1 has several off-target effects, including blocking of a delayedrectifying K + channel at the plasma membrane and inhibition of mitochondrial outer membrane permeabilization in a Drp1-independent manner (Rosdah et al, 2016;Kushnareva et al, 2012;So et al, 2012). Second, glutamate excitotoxicity causes mitochondrial fission through a Drp1-independent mechanism in primary hippocampal cultures (Young et al, 2010).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Impaired assembly of mitotic spindle due to a hyperfused mitochondrial network after mdivi-1 treatment induces aneuploidy and consequent tumor cell apoptosis [22,159]. Despite the strong resistance to apoptosis often associated with an elongated mitochondrial network induced by mdivi-1 treatment particularly in cardiovascular cells and neurons [160], in brain tumor initiating cells (BTICs) (where Drp1 levels are upregulated), mdivi-1 treatment induces apoptosis, thus reducing BTICs tumor formation capacity [161]. Similarly, mdivi-1 increases the sensitivity of melanoma, lung cancer and osteosarcoma cells to Tumor Necrosis Factor-related apoptosis-inducer ligand (TRAIL)-induced caspase-dependent apoptosis [162], even though independently of its inhibitory action on Drp1 [163].…”

“…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).…”

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

“…Human Drp1 was less active than its yeast homologue and incapable of self-assembly, leading to speculation that the human protein was folded incorrectly. Nevertheless, mdivi-1 caused elongation of mammalian mitochondria in COS cells within an hour (Cassidy-Stone et al, 2008) and lengthened mitochondria in several additional studies (Rosdah et al, 2016). Consequently, mdivi-1 is widely considered to be a small molecule inhibitor of mitochondrial fission that specifically targets Drp1.…”