Open Close
Reference
Citation
El Fissi, N., Rojo, M., Aouane, A., Karatas, E., Poliacikova, G., David, C., Royet, J., Rival, T. (2018). Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy.  EMBO Rep. 19(8): e45241.
FlyBase ID
FBrf0239694
Publication Type
Research paper
Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by dominant alleles of the mitochondrial pro-fusion factor Mitofusin 2 (MFN2). To address the consequences of these mutations on mitofusin activity and neuronal function, we generate Drosophila models expressing in neurons the two most frequent substitutions (R94Q and R364W, the latter never studied before) and two others localizing to similar domains (T105M and L76P). All alleles trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism and increased mtDNA mutations, but they differently alter mitochondrial morphology and organization. Substitutions near or within the GTPase domain (R94Q, T105M) result in loss of function and provoke aggregation of unfused mitochondria. In contrast, mutations within helix bundle 1 (R364W, L76P) enhance mitochondrial fusion, as demonstrated by the rescue of mitochondrial alterations and locomotor deficits by over-expression of the fission factor DRP1. In conclusion, we show that both dominant negative and dominant active forms of mitofusin can cause CMT2A-associated defects and propose for the first time that excessive mitochondrial fusion drives CMT2A pathogenesis in a large number of patients.

PubMed ID
PubMed Central ID
PMC6073211 (PMC) (EuropePMC)
Related Publication(s)
Erratum

Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy.
El Fissi et al., 2020, EMBO Rep. 21(7): e50703 [FBrf0246109]

Note

Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A.
Ueda and Ishihara, 2018, EMBO Rep. 19(8): e46502 [FBrf0241335]

Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    EMBO Rep.
    Title
    EMBO Reports
    Publication Year
    2000-
    ISBN/ISSN
    1469-221X 1469-3178
    Data From Reference