Universität zu Köln

Joaquim, Mariana ORCID: 0000-0003-4669-4493, Altin, Selver, Bulimaga, Maria-Bianca ORCID: 0000-0002-2050-6098, Simões, Tânia, Nolte, Hendrik ORCID: 0000-0003-1560-5099, Bader, Verian ORCID: 0000-0001-5260-4728, Franchino, Camilla Aurora ORCID: 0009-0002-4502-6514, Plouzennec, Solenn, Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Marchesan, Elena, Hofmann, Kay ORCID: 0000-0002-2289-9083, Krüger, Marcus ORCID: 0000-0002-5846-6941, Ziviani, Elena, Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517, Chevrollier, Arnaud, Winklhofer, Konstanze F. ORCID: 0000-0002-7256-8231, Motori, Elisa ORCID: 0000-0001-5997-6866, Odenthal, Margarete ORCID: 0000-0002-2424-0960 and Escobar-Henriques, Mafalda ORCID: 0000-0002-0879-3119 (2025). Mitofusin 2 displays fusion-independent roles in proteostasis surveillance. Nature Communications, 16 (1). p. 1501. Springer Nature. ISSN 2041-1723

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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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Joaquim, Mariana UNSPECIFIED https://orcid.org/0000-0003-4669-4493 UNSPECIFIED Altin, Selver UNSPECIFIED UNSPECIFIED UNSPECIFIED Bulimaga, Maria-Bianca UNSPECIFIED https://orcid.org/0000-0002-2050-6098 UNSPECIFIED Simões, Tânia UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED https://orcid.org/0000-0003-1560-5099 UNSPECIFIED Bader, Verian UNSPECIFIED https://orcid.org/0000-0001-5260-4728 UNSPECIFIED Franchino, Camilla Aurora UNSPECIFIED https://orcid.org/0009-0002-4502-6514 UNSPECIFIED Plouzennec, Solenn UNSPECIFIED UNSPECIFIED UNSPECIFIED Szczepanowska, Karolina UNSPECIFIED https://orcid.org/0000-0003-4689-2350 UNSPECIFIED Marchesan, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Kay UNSPECIFIED https://orcid.org/0000-0002-2289-9083 UNSPECIFIED Krüger, Marcus UNSPECIFIED https://orcid.org/0000-0002-5846-6941 UNSPECIFIED Ziviani, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED https://orcid.org/0000-0002-5472-3517 UNSPECIFIED Chevrollier, Arnaud UNSPECIFIED UNSPECIFIED UNSPECIFIED Winklhofer, Konstanze F. UNSPECIFIED https://orcid.org/0000-0002-7256-8231 UNSPECIFIED Motori, Elisa UNSPECIFIED https://orcid.org/0000-0001-5997-6866 UNSPECIFIED Odenthal, Margarete UNSPECIFIED https://orcid.org/0000-0002-2424-0960 UNSPECIFIED Escobar-Henriques, Mafalda UNSPECIFIED https://orcid.org/0000-0002-0879-3119 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-792310
Identification Number:	10.1038/s41467-025-56673-5
Journal or Publication Title:	Nature Communications
Volume:	16
Number:	1
Page Range:	p. 1501
Date:	10 February 2025
Publisher:	Springer Nature
ISSN:	2041-1723
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers External institution Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79231