{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:12:24Z","timestamp":1790745144695,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cyprus Telethon","award":["33173176"],"award-info":[{"award-number":["33173176"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in MFN2 encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel MFN2K357T mutation associated with early onset, autosomal dominant severe CMT2A, we generated a knock-in mouse model. While Mfn2K357T\/K357T mouse pups were postnatally lethal, Mfn2+\/K357T heterozygous mice were asymptomatic and had no histopathological changes in their sciatic nerves up to 10 months of age. However, immunofluorescence analysis of Mfn2+\/K357T mice revealed aberrant mitochondrial clustering in the sciatic nerves from 6 months of age, in optic nerves from 8 months, and in lumbar spinal cord white matter at 10 months, along with microglia activation. Ultrastructural analyses confirmed dysmorphic mitochondrial aggregates in sciatic and optic nerves. After exposure of 6-month-old mice to lipopolysaccharide, Mfn2+\/K357T mice displayed a higher immune response, a more severe motor impairment, and increased CNS inflammation, microglia activation, and macrophage infiltrates. Overall, ubiquitous Mfn2K357T expression renders the CNS and peripheral nerves of Mfn2+\/K357T mice more susceptible to mitochondrial clustering, and augments their response to inflammation, modeling some cellular mechanisms that may be relevant for the development of neuropathy in patients with CMT2A.<\/jats:p>","DOI":"10.3390\/ijms222111569","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T23:54:33Z","timestamp":1635292473000},"page":"11569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4505-8164","authenticated-orcid":false,"given":"Filippos","family":"Stavropoulos","sequence":"first","affiliation":[{"name":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, 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":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-6932","authenticated-orcid":false,"given":"Louiza","family":"Potamiti","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-1299","authenticated-orcid":false,"given":"Alexia","family":"Kagiava","sequence":"additional","affiliation":[{"name":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-3552","authenticated-orcid":false,"given":"Mihalis I.","family":"Panayiotidis","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of GreenBio Science and Technology, Seoul National University, Pyeongchang 25354, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9491-5740","authenticated-orcid":false,"given":"Su Cheong","family":"Yeom","sequence":"additional","affiliation":[{"name":"Graduate School of International Agricultural Technology and Institute of GreenBio Science and Technology, Seoul National University, Pyeongchang 25354, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Young","family":"Lee","sequence":"additional","affiliation":[{"name":"ToolGen Inc., Seoul 08501, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kleopas A.","family":"Kleopa","sequence":"additional","affiliation":[{"name":"Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Center for Neuromuscular Disorders and Center for Multiple Sclerosis and Related Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1399-0004.1974.tb00638.x","article-title":"Genetic and clinical aspects of Charcot-Marie-Tooth\u2019s disease","volume":"6","author":"Skre","year":"1974","journal-title":"Clin. 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