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. KitsisEvripidis Gavathiotis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3775
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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