Direct Small Molecule Activation of Mitofusins

Zacharioudakis, E.; Biris, N.; Garner, T.; Chen, Y.; Pekson, R.; Dhingra, R.; Santulli, G.; Kirshenbaum, L.; Kitsis, R.; Gavathiotis, E.

doi:10.1101/301713

bioRxiv · 10.1101/301713

Direct Small Molecule Activation of Mitofusins

Zacharioudakis, E.·Biris, N.·Garner, T.·Chen, Y.·Pekson, R.·Dhingra, R.·Santulli, G.·Kirshenbaum, L.·Kitsis, R.·Gavathiotis, E.

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Abstract

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.

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Zacharioudakis, E., Biris, N., Garner, T., Chen, Y., Pekson, R., Dhingra, R., Santulli, G., Kirshenbaum, L., Kitsis, R., Gavathiotis, E.. 2018-04-17. Direct Small Molecule Activation of Mitofusins. https://doi.org/10.1101/301713

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