{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:59:27Z","timestamp":1760144367919,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["FP7-IDEAS-ERC 311610"],"award-info":[{"award-number":["FP7-IDEAS-ERC 311610"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"INSERM\u2014AVENIR","award":["FP7-IDEAS-ERC 311610"],"award-info":[{"award-number":["FP7-IDEAS-ERC 311610"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Demyelinating Charcot\u2013Marie\u2013Tooth 4G (CMT4G) results from a recessive mutation in the 5\u2032UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.<\/jats:p>","DOI":"10.3390\/ijms25084364","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T11:53:53Z","timestamp":1713182033000},"page":"4364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Hexokinase 1 5\u2032-UTR Mutation in Charcot\u2013Marie\u2013Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering"],"prefix":"10.3390","volume":"25","author":[{"given":"Maria","family":"Ceprian","sequence":"first","affiliation":[{"name":"Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raul","family":"Juntas-Morales","sequence":"additional","affiliation":[{"name":"Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, H\u00f4pital Universitaire Gui de Chauliac, 34295 Montpellier, France"},{"name":"Unidad Neuromuscular, Servicio de Neurologia, Hospital Universitario Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Campbell","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Walther-Louvier","sequence":"additional","affiliation":[{"name":"Service de Neuropediatrie, H\u00f4pital Universitaire Gui de Chauliac, 34295 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Rivier","sequence":"additional","affiliation":[{"name":"Service de Neuropediatrie, H\u00f4pital Universitaire Gui de Chauliac, 34295 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Camu","sequence":"additional","affiliation":[{"name":"Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, H\u00f4pital Universitaire Gui de Chauliac, 34295 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Esselin","sequence":"additional","affiliation":[{"name":"Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, H\u00f4pital Universitaire Gui de Chauliac, 34295 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1012-9783","authenticated-orcid":false,"given":"Andoni","family":"Echaniz-Laguna","sequence":"additional","affiliation":[{"name":"AEL, Department of Neurology, Bicetre University Hospital, Paris Saclay University, 94270 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4054-2838","authenticated-orcid":false,"given":"Tanya","family":"Stojkovic","sequence":"additional","affiliation":[{"name":"Service de Neurologie, H\u00f4pital Universitaire Piti\u00e9-Salp\u00eatri\u00e8re, 75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Bouhour","sequence":"additional","affiliation":[{"name":"Service de Neurologie, H\u00f4pital Universitaire Lyon, 69500 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Latour","sequence":"additional","affiliation":[{"name":"Centre de Biologie Est Biochimie et Biologie Mol\u00e9culaire, Hospices Civils de Lyon, 69677 Bron, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Tricaud","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France"},{"name":"I-Stem, UEVE\/UPS U861, INSERM, AFM, 91100 Corbeil-Essonnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s13353-013-0168-7","article-title":"Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma\/Gypsies in Slovakia","volume":"54","author":"Gabrikova","year":"2013","journal-title":"J. Appl. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/cge.12015","article-title":"Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: The hereditary motor and sensory neuropathy-Russe in depth","volume":"83","author":"Sevilla","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/cge.12745","article-title":"HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL","volume":"90","author":"Mazanec","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/ana.1137","article-title":"Hereditary motor and sensory neuropathy-russe: New autosomal recessive neuropathy in balkan gypsies","volume":"50","author":"Thomas","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/ejhg.2009.99","article-title":"A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy\u2014Russe (HMSNR)","volume":"17","author":"Hantke","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"320","DOI":"10.2174\/1874467209666160112123036","article-title":"Role of Hexokinase and VDAC in Neurological Disorders","volume":"9","author":"Rosa","year":"2016","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0925-4439(96)00080-4","article-title":"Molecular bases of hexokinase deficiency","volume":"1360","author":"Bianchi","year":"1997","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1006\/bcmd.2001.0454","article-title":"Downeast Anemia (dea), a New Mouse Model of Severe Nonspherocytic Hemolytic Anemia Caused by Hexokinase (HKI) Deficiency","volume":"27","author":"Peters","year":"2001","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4633","DOI":"10.1038\/onc.2008.114","article-title":"Disruption of the hexokinase\u2013VDAC complex for tumor therapy","volume":"27","author":"Galluzzi","year":"2008","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.3389\/fphys.2017.00460","article-title":"Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target","volume":"8","author":"Camara","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tricaud, N., Gautier, B., Berthelot, J., Gonzalez, S., and Van Hameren, G. (2022). Traumatic and Diabetic Schwann Cell Demyelination Is Triggered by a Transient Mitochondrial Calcium Release through Voltage Dependent Anion Channel 1. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061447"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.15698\/cst2017.10.104","article-title":"VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress","volume":"1","author":"Maldonado","year":"2017","journal-title":"Cell Stress"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","article-title":"Calcium Signaling","volume":"131","author":"Clapham","year":"2007","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bryan, N., and Raisch, K.P. (2015). Identification of a mitochondrial-binding site on the N-terminal end of hexokinase II. Biosci. Rep., 35.","DOI":"10.1042\/BSR20150047"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Magr\u00ec, A., Belfiore, R., Reina, S., Tomasello, M.F., Di Rosa, M.C., Guarino, F., Leggio, L., De Pinto, V., and Messina, A. (2016). Hexokinase I N-terminal based peptide prevents the VDAC1-SOD1 G93A interaction and re-establishes ALS cell viability. Sci. Rep., 6.","DOI":"10.1038\/srep34802"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11633","DOI":"10.1021\/acs.jmedchem.2c00411","article-title":"Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 to Block Peripheral Nerve Demyelination","volume":"65","author":"Gautier","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1016\/j.phytochem.2009.06.007","article-title":"Methyl jasmonate: A plant stress hormone as an anti-cancer drug","volume":"70","author":"Cohen","year":"2009","journal-title":"Phytochemistry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1038\/onc.2008.108","article-title":"Methyl jasmonate binds to and detaches mitochondria-bound hexokinase","volume":"27","author":"Goldin","year":"2008","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cesari, I.M., Carvalho, E., Rodrigues, M.F., Mendon\u00e7a, B.d.S., Am\u00f4edo, N.D., and Rumjanek, F.D. (2014). Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis. Int. J. Cell Biol., 2014.","DOI":"10.1155\/2014\/572097"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1093\/abbs\/gmr075","article-title":"Differential mitochondrial calcium responses in different cell types detected with a mitochondrial calcium fluorescent indicator, mito-GCaMP2","volume":"43","author":"Chen","year":"2011","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1073\/pnas.0509378103","article-title":"Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2","volume":"103","author":"Tallini","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1177\/08830738060210010401","article-title":"Early Clinical and Electrophysiologic Features of the Two Most Common Autosomal Recessive Forms of Charcot-Marie-Tooth Disease in the Roma (Gypsies)","volume":"21","author":"Guergueltcheva","year":"2006","journal-title":"J. Child Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:28:21Z","timestamp":1760106501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,15]]},"references-count":22,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25084364"],"URL":"https:\/\/doi.org\/10.3390\/ijms25084364","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,4,15]]}}}