The Hexokinase 1 5'-UTR Mutation in Charcot-Marie-Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering.

Autor: Ceprian M; Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France., Juntas-Morales R; Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, Hôpital Universitaire Gui de Chauliac, 34295 Montpellier, France.; Unidad Neuromuscular, Servicio de Neurologia, Hospital Universitario Vall d'Hebron, 08035 Barcelona, Spain., Campbell G; Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France., Walther-Louvier U; Service de Neuropediatrie, Hôpital Universitaire Gui de Chauliac, 34295 Montpellier, France., Rivier F; Service de Neuropediatrie, Hôpital Universitaire Gui de Chauliac, 34295 Montpellier, France., Camu W; Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, Hôpital Universitaire Gui de Chauliac, 34295 Montpellier, France., Esselin F; Clinique du Motoneurone, Explorations Fonctionnelles Neurologiques, Service de Neurologie, Hôpital Universitaire Gui de Chauliac, 34295 Montpellier, France., Echaniz-Laguna A; AEL, Department of Neurology, Bicetre University Hospital, Paris Saclay University, 94270 Paris, France., Stojkovic T; Service de Neurologie, Hôpital Universitaire Pitié-Salpêtrière, 75013 Paris, France., Bouhour F; Service de Neurologie, Hôpital Universitaire Lyon, 69500 Lyon, France., Latour P; Centre de Biologie Est Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, 69677 Bron, France., Tricaud N; Institute for Neuroscience of Montpellier (INM), University Montpellier, INSERM, 34091 Montpellier, France.; I-Stem, UEVE/UPS U861, INSERM, AFM, 91100 Corbeil-Essonnes, France.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2024 Apr 15; Vol. 25 (8). Date of Electronic Publication: 2024 Apr 15.
DOI: 10.3390/ijms25084364
Abstrakt: Demyelinating Charcot-Marie-Tooth 4G (CMT4G) results from a recessive mutation in the 5'UTR 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.
Databáze: MEDLINE
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