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

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

doi:10.1093/hmg/ddz008

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

Journal article

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Peer reviewed

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

Delfina Larrea, Marta Pera, Adriano Gonnelli, Rubén Quintana-Cabrera, H Orhan Akman, Cristina Guardia-Laguarta, Kevin R Velasco, Estela Area-Gomez, Federica Dal Bello, Diego De Stefani, …

Human molecular genetics, Vol.28(11), pp.1782-1800

06/01/2019

DOI: 10.1093/hmg/ddz008

PMCID: PMC6522073

PMID: 30649465

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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.

Mutation

Severity of Illness Index

Endoplasmic Reticulum - genetics

Mitochondrial Dynamics - genetics

Humans

Middle Aged

Oxidative Phosphorylation

Endoplasmic Reticulum - metabolism

Genotype

Male

Mitochondria - metabolism

Mitochondrial Proteins - genetics

Charcot-Marie-Tooth Disease - pathology

Charcot-Marie-Tooth Disease - genetics

Mitochondrial Membranes - metabolism

Mitochondria - genetics

GTP Phosphohydrolases - genetics

Adult

Female

Energy Metabolism - genetics

Charcot-Marie-Tooth Disease - metabolism

Fibroblasts - metabolism

Details

Title: Subtitle: MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics
Creators: Delfina Larrea - Department of Neurology, Columbia University Medical Center, New York, NY, USA
Marta Pera - Department of Neurology, Columbia University Medical Center, New York, NY, USA
Adriano Gonnelli - Department of Biology, University of Padova 35131, Italy
Rubén Quintana-Cabrera - Department of Biology, University of Padova 35131, Italy
H Orhan Akman - Department of Neurology, Columbia University Medical Center, New York, NY, USA
Cristina Guardia-Laguarta - Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
Kevin R Velasco - Department of Neurology, Columbia University Medical Center, New York, NY, USA
Estela Area-Gomez - Department of Neurology, Columbia University Medical Center, New York, NY, USA
Federica Dal Bello - Department of Biology, University of Padova 35131, Italy
Diego De Stefani - Department of Biomedical Sciences, University of Padova, Italy
Rita Horvath - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
Michael E Shy - Department of Neurology, University of Iowa, Iowa City, IA, USA
Eric A Schon - Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
Marta Giacomello - Department of Biology, University of Padova 35131, Italy
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.28(11), pp.1782-1800
DOI: 10.1093/hmg/ddz008
PMID: 30649465
PMCID: PMC6522073
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: MR/N025431/2 / Medical Research Council K01 AG045335 / NIA NIH HHS R01 AG056387 / NIA NIH HHS MR/N010035/1 / Medical Research Council G1000848 / Medical Research Council MR/N025431/1 / Medical Research Council
Language: English
Date published: 06/01/2019
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984070314202771

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