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Direct Small Molecule Activation of Mitofusins

Emmanouil Zacharioudakis, Nikolaos Biris, Thomas P. Garner, Yun Chen, Ryan Pekson, Rimpy Dhingra, Gaetano Santulli, Lorrie A. Kirshenbaum, Richard N. Kitsis, Evripidis Gavathiotis
doi: https://doi.org/10.1101/301713
Emmanouil Zacharioudakis
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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Nikolaos Biris
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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Thomas P. Garner
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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Yun Chen
2Department of Medicine and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, 10461 USA
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Ryan Pekson
2Department of Medicine and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, 10461 USA
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Rimpy Dhingra
3Department of Physiology and Pathophysiology and Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba Canada and Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, R2H2A6 Canada
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Gaetano Santulli
4Department of Medicine, Wilf Family Cardiovascular Research Institute, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461 USA
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Lorrie A. Kirshenbaum
3Department of Physiology and Pathophysiology and Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba Canada and Institute of Cardiovascular Sciences, St. Boniface Research Centre, Winnipeg, Manitoba, R2H2A6 Canada
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Richard N. Kitsis
5Department of Medicine, Department of Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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  • For correspondence: evripidis.gavathiotis@einstein.yu.edu richard.kitsis@einstein.yu.edu
Evripidis Gavathiotis
6Department of Biochemistry, Department of Medicine, Wilf Family Cardiovascular Research Institute, and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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  • For correspondence: evripidis.gavathiotis@einstein.yu.edu richard.kitsis@einstein.yu.edu
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Summary

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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Posted April 17, 2018.
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Direct Small Molecule Activation of Mitofusins
Emmanouil Zacharioudakis, Nikolaos Biris, Thomas P. Garner, Yun Chen, Ryan Pekson, Rimpy Dhingra, Gaetano Santulli, Lorrie A. Kirshenbaum, Richard N. Kitsis, Evripidis Gavathiotis
bioRxiv 301713; doi: https://doi.org/10.1101/301713
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Direct Small Molecule Activation of Mitofusins
Emmanouil Zacharioudakis, Nikolaos Biris, Thomas P. Garner, Yun Chen, Ryan Pekson, Rimpy Dhingra, Gaetano Santulli, Lorrie A. Kirshenbaum, Richard N. Kitsis, Evripidis Gavathiotis
bioRxiv 301713; doi: https://doi.org/10.1101/301713

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