{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T02:52:32Z","timestamp":1781664752971,"version":"3.54.5"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Peripheral Nervous Sys"],"published-print":{"date-parts":[[2023,9]]},"abstract":"Abstract<\/jats:title>Background and aims<\/jats:title>Mitofusin 1 (MFN1) and MFN2 are outer mitochondrial membrane fusogenic proteins regulating mitochondrial network morphology. MFN2<\/jats:italic> mutations cause Charcot\u2010Marie\u2010Tooth type 2A (CMT2A), an axonal neuropathy characterized by mitochondrial fusion defects, which in the case of a GTPase domain mutant, were rescued following wild\u2010type MFN1\/2<\/jats:italic> (MFN1\/2<\/jats:italic>WT<\/jats:italic><\/jats:sup>) overexpression. In this study, we compared the therapeutic efficiency between MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> and MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup> overexpression in correcting mitochondrial defects induced by the novel MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup> mutation located in the highly conserved R3 region.<\/jats:p><\/jats:sec>Methods<\/jats:title>Constructs expressing either MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup>, MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup>, or MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> under the ubiquitous chicken \u03b2<\/jats:italic>\u2010actin hybrid (CBh<\/jats:italic>) promoter were generated. Flag or myc tag was used for their detection. Differentiated SH\u2010SY5Y cells were single transfected with MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup>, MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup>, or MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup>, as well as double transfected with MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup>\/MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup> or MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup>\/MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup>.<\/jats:p><\/jats:sec>Results<\/jats:title>SH\u2010SY5Y cells transfected with MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup> exhibited severe perinuclear mitochondrial clustering with axon\u2010like processes devoid of mitochondria. Single transfection with MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> resulted in a more interconnected mitochondrial network than transfection with MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup>, accompanied by mitochondrial clusters. Double transfection of MFN2<\/jats:italic>K357T<\/jats:italic><\/jats:sup> with either MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> or MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup> resolved the mutant\u2010induced mitochondrial clusters and led to detectable mitochondria throughout the axon\u2010like processes. MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> showed higher efficacy than MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup> in rescuing these defects.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>These results further demonstrate the higher potential of MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup> over MFN2<\/jats:italic>WT<\/jats:italic><\/jats:sup> overexpression to rescue CMT2A\u2010induced mitochondrial network abnormalities due to mutations outside the GTPase domain. This higher phenotypic rescue conferred by MFN1<\/jats:italic>WT<\/jats:italic><\/jats:sup>, possibly due to its higher mitochondrial fusogenic ability, may be applied to different CMT2A cases regardless of the MFN2<\/jats:italic> mutation type.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jns.12564","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T17:30:04Z","timestamp":1684863004000},"page":"329-340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitofusin 1 overexpression rescues the abnormal mitochondrial dynamics caused by the Mitofusin 2 K357T<\/scp> mutation in vitro"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4505-8164","authenticated-orcid":false,"given":"Filippos","family":"Stavropoulos","sequence":"first","affiliation":[{"name":"Department of Neuroscience The Cyprus Institute of Neurology and Genetics Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-7973","authenticated-orcid":false,"given":"Elena","family":"Georgiou","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The Cyprus Institute of Neurology and Genetics Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Schiza","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The Cyprus Institute of Neurology and Genetics Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaughn","family":"Bell","sequence":"additional","affiliation":[{"name":"Board of Governors Regenerative Medicine Institute Cedars\u2010Sinai Medical Center Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0100-8376","authenticated-orcid":false,"given":"Robert H.","family":"Baloh","sequence":"additional","affiliation":[{"name":"Global Head of Neuroscience Novartis Institutes for BioMedical Research Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-8094","authenticated-orcid":false,"given":"Kleopas A.","family":"Kleopa","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The Cyprus Institute of Neurology and Genetics Nicosia Cyprus"},{"name":"Center for Neuromuscular Disorders and Center for Multiple Sclerosis and Related Disorders The Cyprus Institute of Neurology and Genetics Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-0823","authenticated-orcid":false,"given":"Irene","family":"Sargiannidou","sequence":"additional","affiliation":[{"name":"Department of Neuroscience The Cyprus Institute of Neurology and Genetics Nicosia 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