Mitofusin 2 displays fusion-independent roles in proteostasis surveillance
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.
Authors
- Aleksandra Trifunović (ORCID: https://orcid.org/0000-0002-5472-3517)
- Marcus Krüger (ORCID: https://orcid.org/0000-0002-5846-6941)
- Mariana Joaquim (ORCID: https://orcid.org/0000-0003-4669-4493)
- Hendrik Nolte (ORCID: https://orcid.org/0000-0003-1560-5099)
- Selver Altin
- Elena Marchesan (ORCID: https://orcid.org/0000-0001-5186-6056)
- Tânia Simões (ORCID: https://orcid.org/0000-0002-5971-4935)
- Arnaud Chevrollier (ORCID: https://orcid.org/0000-0002-5135-6643)
- Karolina Szczepanowska (ORCID: https://orcid.org/0000-0003-4689-2350)
- Elisa Motori (ORCID: https://orcid.org/0000-0001-5997-6866)
- Margarete Odenthal (ORCID: https://orcid.org/0000-0002-2424-0960)
- Verian Bader (ORCID: https://orcid.org/0000-0001-5260-4728)
- Mafalda Escobar‐Henriques (ORCID: https://orcid.org/0000-0002-0879-3119)
- Elena Ziviani (ORCID: https://orcid.org/0000-0002-0864-8309)
- Konstanze F. Winklhofer (ORCID: https://orcid.org/0000-0002-7256-8231)
- Camilla Aurora Franchino (ORCID: https://orcid.org/0009-0002-4502-6514)
- Kay Hofmann (ORCID: https://orcid.org/0000-0002-2289-9083)
- Maria-Bianca Bulimaga
- Solenn Plouzennec
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Padua (IT)
- Inserm (FR)
- University of Cologne (DE)
- Polish Institute of International Affairs (PL)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Max Planck Institute for Biology of Ageing (DE)
- Université d'Angers (FR)
- Ruhr University Bochum (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1038/s41467-025-56673-5
- Citations
- 11
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- Boehringer Ingelheim
- Deutsche Forschungsgemeinschaft
- Fritz Thyssen Stiftung