Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target

Ira Buntenbroich; Vincent Anton; Daniel Perez-Hernandez; Tânia Simões; Felix Gaedke; Astrid Schauss; Gunnar Dittmar; Jan Riemer; Mafalda Escobar-Henriques

doi:10.1016/j.isci.2023.107014

Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target

iScience. 2023 Jun 7;26(7):107014. doi: 10.1016/j.isci.2023.107014. eCollection 2023 Jul 21.

Authors

Affiliations

¹ Institute for Genetics,University of Cologne, Cologne 50931, Germany.
² Proteomics of Cellular Signaling, Luxembourg Institute of Health, Strassen 1445, Luxembourg.
³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
⁴ Institute for Biochemistry, University of Cologne, Cologne 50931, Germany.
⁵ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50931, Germany.

Abstract

Defects in mitochondrial fusion are at the base of many diseases. Mitofusins power membrane-remodeling events via self-interaction and GTP hydrolysis. However, how exactly mitofusins mediate fusion of the outer membrane is still unclear. Structural studies enable tailored design of mitofusin variants, providing valuable tools to dissect this stepwise process. Here, we found that the two cysteines conserved between yeast and mammals are required for mitochondrial fusion, revealing two novel steps of the fusion cycle. C381 is dominantly required for the formation of the trans-tethering complex, before GTP hydrolysis. C805 allows stabilizing the Fzo1 protein and the trans-tethering complex, just prior to membrane fusion. Moreover, proteasomal inhibition rescued Fzo1 C805S levels and membrane fusion, suggesting a possible application for clinically approved drugs. Together, our study provides insights into how assembly or stability defects in mitofusins might cause mitofusin-associated diseases and uncovers potential therapeutic intervention by proteasomal inhibition.

Keywords: Biological sciences; Cell biology; Genetics; Molecular biology.