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MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.

Published version
Peer-reviewed

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Type

Article

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Authors

Larrea, Delfina 
Pera, Marta 
Gonnelli, Adriano 
Quintana-Cabrera, Rubén 
Akman, H Orhan 

Abstract

Charcot-Marie-Tooth disease (CMT) type 2A is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)-mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior. To date, no studies have been performed to address whether mutations in MFN2 in CMT2A patient cells affect MAM function, which might provide insight into pathogenesis. Using fibroblasts from three CMT2AMFN2 patients with different mutations in MFN2, we found that some, but not all, examined aspects of ER-mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. Notably, however, respiratory chain function in those cells was unimpaired. Our results suggest that CMT2AMFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.

Description

Keywords

Adult, Charcot-Marie-Tooth Disease, Endoplasmic Reticulum, Energy Metabolism, Female, Fibroblasts, GTP Phosphohydrolases, Genotype, Humans, Male, Middle Aged, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membranes, Mitochondrial Proteins, Mutation, Oxidative Phosphorylation, Severity of Illness Index

Journal Title

Hum Mol Genet

Conference Name

Journal ISSN

0964-6906
1460-2083

Volume Title

28

Publisher

Oxford University Press (OUP)
Sponsorship
Wellcome Trust (109915_A_15_Z)
Medical Research Council (MR/N025431/2)