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

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 O ₂ 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 (K _i>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.

eTOC

Bordt, Clerc et al. show that the putative Drp1 inhibitor mdivi-1 reversibly inhibits mitochondrial complex I without impairing Drp1 GTPase activity or lengthening mitochondria. Mdivi-1 attenuates mitochondrial reactive oxygen species production under conditions relevant to ischemia/reperfusion injury. These mechanisms may provide an alternative explanation for some of mdivi-1’s in vivo effects.