Modulating mitofusins to control mitochondrial function and signaling

Emmanouil Zacharioudakis, Bogos Agianian, Vasantha Kumar Mv, Nikolaos Biris, Thomas P. Garner, Inna Rabinovich-Nikitin, Amanda T. Ouchida, Victoria Margulets, Lars Ulrik Nordstrøm, Joel S. Riley, Igor Dolgalev, Yun Chen, Andre J. H. Wittig, Ryan Pekson, Chris Mathew, Peter Wei, Aristotelis Tsirigos, Stephen W. G. Tait, Lorrie A. Kirshenbaum, Richard N. Kitsis and Evripidis Gavathiotis ()
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Emmanouil Zacharioudakis: Albert Einstein College of Medicine
Bogos Agianian: Albert Einstein College of Medicine
Vasantha Kumar Mv: Albert Einstein College of Medicine
Nikolaos Biris: Albert Einstein College of Medicine
Thomas P. Garner: Albert Einstein College of Medicine
Inna Rabinovich-Nikitin: University of Manitoba
Amanda T. Ouchida: Albert Einstein College of Medicine
Victoria Margulets: University of Manitoba
Lars Ulrik Nordstrøm: Albert Einstein College of Medicine
Joel S. Riley: Cancer Research UK Beatson Institute
Igor Dolgalev: New York University School of Medicine
Yun Chen: Albert Einstein College of Medicine
Andre J. H. Wittig: Albert Einstein College of Medicine
Ryan Pekson: Albert Einstein College of Medicine
Chris Mathew: Albert Einstein College of Medicine
Peter Wei: Albert Einstein College of Medicine
Aristotelis Tsirigos: New York University School of Medicine
Stephen W. G. Tait: Cancer Research UK Beatson Institute
Lorrie A. Kirshenbaum: University of Manitoba
Richard N. Kitsis: Albert Einstein College of Medicine
Evripidis Gavathiotis: Albert Einstein College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31324-1

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DOI: 10.1038/s41467-022-31324-1

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