Universität zu Köln

Joaquim, Mariana ORCID: 0000-0003-4669-4493, Bulimaga, Maria-Bianca ORCID: 0000-0002-2050-6098, Mohn, Marie A. ORCID: 0009-0007-8464-6982, Plouzennec, Solenn, Osinski, Leon ORCID: 0009-0007-6143-0484, Altin, Selver, Mahabir, Esther ORCID: 0000-0002-9573-5127, Chevrollier, Arnaud and Escobar-Henriques, Mafalda ORCID: 0000-0002-0879-3119 (2025). Charcot–Marie–Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death. Journal of Cell Science, 138 (18). pp. 1-16. Company of Biologists Limited. ISSN 0021-9533

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Abstract

[Artikel-Nr.: jcs263691] The neuropathy Charcot–Marie–Tooth (CMT) is an incurable disease with a lack of genotype–phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Joaquim, Mariana UNSPECIFIED https://orcid.org/0000-0003-4669-4493 UNSPECIFIED Bulimaga, Maria-Bianca UNSPECIFIED https://orcid.org/0000-0002-2050-6098 UNSPECIFIED Mohn, Marie A. UNSPECIFIED https://orcid.org/0009-0007-8464-6982 UNSPECIFIED Plouzennec, Solenn UNSPECIFIED UNSPECIFIED UNSPECIFIED Osinski, Leon UNSPECIFIED https://orcid.org/0009-0007-6143-0484 UNSPECIFIED Altin, Selver UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahabir, Esther UNSPECIFIED https://orcid.org/0000-0002-9573-5127 UNSPECIFIED Chevrollier, Arnaud UNSPECIFIED UNSPECIFIED UNSPECIFIED Escobar-Henriques, Mafalda UNSPECIFIED https://orcid.org/0000-0002-0879-3119 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-811732
Identification Number:	10.1242/jcs.263691
Journal or Publication Title:	Journal of Cell Science
Volume:	138
Number:	18
Page Range:	pp. 1-16
Number of Pages:	16
Date:	15 September 2025
Publisher:	Company of Biologists Limited
ISSN:	0021-9533
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	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:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Charcot–Marie–Tooth ; CMT2A ; MFN2 ; Apoptosis ; Cell death ; Mitochondria ; Fusion English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81173