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.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Calcium*/metabolism ; Charcot-Marie-Tooth Disease*/genetics ; Charcot-Marie-Tooth Disease*/metabolism ; Hexokinase*/genetics ; Hexokinase*/metabolism ; Mitochondria*/metabolism ; Mitochondria*/genetics ; Voltage-Dependent Anion Channel 1*/metabolism ; Voltage-Dependent Anion Channel 1*/genetics; Adolescent ; Adult ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; 5' Untranslated Regions/genetics ; HEK293 Cells ; Mutation ; Protein Binding

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.

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FP7-IDEAS-ERC 311610 International ERC_ European Research Council

Keywords: CMT4G; Hexokinase I; VDAC; mitochondria

0 (HK1 protein, human)

Date Created: 20240427 Date Completed: 20240427 Latest Revision: 20240520

20240520

PMC11050395

10.3390/ijms25084364

38673950