To mdivi‐1 or not to mdivi‐1: Is that the question?

Abstract

The fission/division and fusion of mitochondria are fundamental aspects of mitochondrial biology. The balance of fission and fusion sets the length of mitochondria in cells to serve their physiological requirements. The fission of mitochondria is markedly induced in many disease states and in response to cellular injury, resulting in the fragmentation of mitochondria into dysfunctional units. The mechanism that drives fission is dependent on the dynamin related protein 1 (Drp1) GTPase. mdivi-1 is a quinazolinone originally described as a selective inhibitor of Drp1, over other dynamin family members, and reported to inhibit mitochondrial fission. A recent study has challenged the activity of mdivi-1 as an inhibitor of Drp1. This study raises serious issues regarding the interpretation of data addressing the effects of mdivi-1 as reflective of the inhibition of Drp1 and thus fission. This commentary considers the evidence for and against mdivi-1 as an inhibitor of Drp1 and presents the following considerations; (1) the activity of mdivi-1 toward Drp1 GTPase activity requires further biochemical investigation, (2) as there is a large body of literature using mdivi-1 in vitro with effects as predicted for inhibition of Drp1 and mitochondrial fission, reviewed herein, the evidence is in favor of mdivi-1’s originally described bioactivity, and (3) until the issue is resolved, experimental interpretations for the effects of mdivi-1 on inhibition of fission in cell and tissue experiments warrants stringent positive controls directly addressing the effects of mdivi-1 on fission.

Mitochondrial Morphofunction in Mammalian Cells

“…of Mdivi1, off-target effects have been described, including inhibition of K + channels and membrane potential in HL-1 murine atrial cardiomyocytes (370) as well as CI inhibition and modulation of mitochondrial ROS production (34,322). The pros and cons of the use of Mdivi1 as a specific DRP1 inhibitor were recently discussed (368). It was concluded that although the current evidence supports the previously described Mdivi1 bioactivity, use of this molecule requires inclusion of stringent positive controls that directly demonstrate its effect on mitochondrial fission.…”

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

“…As high concentrations of mdivi-1 (50 μM) might have unexpected side effects, 30 Mdivi-1 treatment decreases glutamine oxidation in H460 cells In addition to glucose, glutamine is another major energy source for cancer cells. 43 In the [U-13 C]glutamine tracing assay, glutamine carbons enter the TCA cycle as fully labelled m + 5 α-KG (containing all five carbons from [U-13 C]glutamine tracer).…”

“…29 Not surprisingly, mdivi-1 has been widely used as a mitochondrial fusion inducer. 30 Studies showed that mdivi-1 treatment altered mitochondrial morphology and cellular oxygen consumption, induced cell death in cancer cells, and limited tumour size in xenograft models. 4,19 However, a recent study showed that mdivi-1 failed to elongate mitochondria or inhibit recombinant human DRP1 GTPase activity in mouse embryonic fibroblasts (MEFs) and normal neurons, and mdivi-1 reversibly inhibited respiration at mitochondrial complex I to decrease the oxygen consumption rate (OCR).…”

Three‐dimensional electron microscopy techniques for unravelling mitochondrial dysfunction in heart failure and identification of new pharmacological targets

“…() who reported that Mdivi‐1 is a reversible inhibitor of Complex I and also leads to ROS production. However, a recent commentary from Smith and Gallo () contends that Mdivi‐1 bioactivity may still hold significant promise as a therapeutic agent for manipulating fission, but that further biochemical studies are required to validate the efficacy and specificity in different disease systems and stage of disease progression. The application of Mdivi‐1 for treating heart disease has been explored by several groups (Ong et al, ; Givvimani et al, ; Sharp et al, ).…”