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

Larrea, Delfina; Pera, Marta; Gonnelli, Adriano; Quintana-Cabrera, Rubén; Akman, H. Orhan; Guardia-Laguarta, Cristina; Velasco, Kevin R.; Area-Gomez, Estela; Dal Bello, Federica; De Stefani, Diego; Horvath, Rita; Shy, Michael E.; Schon, Eric A.; Giacomello, Marta

doi:10.1093/hmg/ddz008

Article (Scientific journals)

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

Larrea, Delfina; Pera, Marta; Gonnelli, Adriano et al.

2019 • In Human Molecular Genetics, 28 (11), p. 1782-1800

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https://hdl.handle.net/2268/248237

DOI
10.1093/hmg/ddz008

PubMed
30649465

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Keywords :

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

Abstract :

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Larrea, Delfina

Pera, Marta

Gonnelli, Adriano

Quintana-Cabrera, Rubén

Akman, H. Orhan

Guardia-Laguarta, Cristina

Velasco, Kevin R.

Area-Gomez, Estela

Dal Bello, Federica ; Université de Liège - ULiège > Cancer-Molecular Angiogenesis Laboratory

De Stefani, Diego

More authors (4 more)

Language :

English

Title :

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

Publication date :

2019

Journal title :

Human Molecular Genetics

ISSN :

0964-6906

eISSN :

1460-2083

Publisher :

Oxford University Press, United Kingdom

Volume :

Issue :

Pages :

1782-1800

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 08 June 2020

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