Modulating mitofusins to control mitochondrial function and signaling

Zacharioudakis, E. et al. (2022) Modulating mitofusins to control mitochondrial function and signaling. Nature Communications, 13, 3775. (doi: 10.1038/s41467-022-31324-1) (PMID:35798717)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Riley, Dr Joel and Tait, Professor Stephen
• Authors: Zacharioudakis, E., Agianian, B., Kumar MV, V., Biris, N., Garner, T. P., Rabinovich-Nikitin, I., Ouchida, A. T., Margulets, V., Nordstrøm, L. U., Riley, J. S., Dolgalev, I., Chen, Y., Wittig, A. J. H., Pekson, R., Mathew, C., Wei, P., Tsirigos, A., Tait, S. W.G., Kirshenbaum, L. A., Kitsis, R. N., and Gavathiotis, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Communications 13: 3775
• Publisher Policy: Reproduced under a Creative Commons License