Mitofusin 2 displays fusion-independent roles in proteostasis surveillance

Mariana Joaquim, Selver Altin, Maria-Bianca Bulimaga, Tânia Simões, Hendrik Nolte, Verian Bader, Camilla Aurora Franchino, Solenn Plouzennec, Karolina Szczepanowska, Elena Marchesan, Kay Hofmann, Marcus Krüger, Elena Ziviani, Aleksandra Trifunovic, Arnaud Chevrollier, Konstanze F. Winklhofer, Elisa Motori, Margarete Odenthal and Mafalda Escobar-Henriques ()
Additional contact information
Mariana Joaquim: University of Cologne
Selver Altin: University of Cologne
Maria-Bianca Bulimaga: University of Cologne
Tânia Simões: University of Cologne
Hendrik Nolte: University of Cologne
Verian Bader: and Cluster of Excellence RESOLV
Camilla Aurora Franchino: University of Cologne
Solenn Plouzennec: SFR ICAT
Karolina Szczepanowska: University of Cologne
Elena Marchesan: University of Padova
Kay Hofmann: University of Cologne
Marcus Krüger: University of Cologne
Elena Ziviani: University of Padova
Aleksandra Trifunovic: University of Cologne
Arnaud Chevrollier: SFR ICAT
Konstanze F. Winklhofer: and Cluster of Excellence RESOLV
Elisa Motori: University of Cologne
Margarete Odenthal: University of Cologne
Mafalda Escobar-Henriques: University of Cologne

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

Date: 2025
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DOI: 10.1038/s41467-025-56673-5

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