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
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