PT  - JOURNAL ARTICLE
AU  - Emmanouil Zacharioudakis
AU  - Nikolaos Biris
AU  - Thomas P. Garner
AU  - Yun Chen
AU  - Ryan Pekson
AU  - Rimpy Dhingra
AU  - Gaetano Santulli
AU  - Lorrie A. Kirshenbaum
AU  - Richard N. Kitsis
AU  - Evripidis Gavathiotis
TI  - Direct Small Molecule Activation of Mitofusins
AID  - 10.1101/301713
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 301713
4099  - http://biorxiv.org/content/early/2018/04/17/301713.short
4100  - http://biorxiv.org/content/early/2018/04/17/301713.full
AB  - Mitochondrial fusion is a physiological process that is regulated by mitofusins on the outer mitochondrial membrane. Conformational plasticity between anti- and pro-tethering conformations of mitofusins permits mitochondrial tethering and subsequent fusion. Here we developed a pharmacophore-based model to rationally manipulate the conformational plasticity of mitofusin 2 and perfomed an in silico small-molecule screen. This enabled the discovery of a direct activator of mitofusins, MASM7, capable of potently promoting mitochondrial fusion. The specificity of the MASM7-mitofusin 2 interaction is highlighted by structure-activity relationships of MASM7 analogues, FRET, NMR and mitochondrial fusion studies using mitofusin mutants. Our study identified the first-in-class direct activator of mitofusins, demonstrating a new paradigm for chemical modulation of mitochondrial fusion and downstream processes.