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.
journal_name
Dev Celljournal_title
Developmental cellauthors
Bordt EA,Clerc P,Roelofs BA,Saladino AJ,Tretter L,Adam-Vizi V,Cherok E,Khalil A,Yadava N,Ge SX,Francis TC,Kennedy NW,Picton LK,Kumar T,Uppuluri S,Miller AM,Itoh K,Karbowski M,Sesaki H,Hill RB,Polster BMdoi
10.1016/j.devcel.2017.02.020subject
Has Abstractpub_date
2017-03-27 00:00:00pages
583-594.e6issue
6eissn
1534-5807issn
1878-1551pii
S1534-5807(17)30116-8journal_volume
40pub_type
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