Mitofusin mutations commonly associated with Charcot-Marie-Tooth neuropathy have opposite effects on mitochondrial fusion

Identification: Rival, Thomas


Description

Mitofusin mutations commonly associated with Charcot Marie Tooth neuropathy have opposite effects on mitochondrial fusion
 
Najla El Fissi1, Manuel Rojo2, Aїcha Aouane1, Claudine David2, Julien Royet1, Thomas Rival 1
1Aix Marseille Univ, CNRS, IBDM, Marseille, France ; 2Univ. Bordeaux, CNRS, Institut de Biochimie et Génétique Cellulaires (IBGC), UMR 5095, 33000 Bordeaux, France
 
Charcot Marie Tooth type 2A (CMT2A) is a dominant hereditary neuropathy caused by mutations in the GTPase Mitofusin (MFN). This mitochondrial outer membrane protein drives mitochondrial fusion a process by which two mitochondria fuse their membranes generating a single entity. To understand how mutations in MFN translate into neuronal dysfunction, we developed drosophila models of CMT2A by generating transgenic flies expressing different MFN alleles frequently identified in patients. As for human, these alleles behave dominantly in flies and impair locomotion. Although all CMT2A alleles trigger mitochondrial synaptic depletion and alter oxidative metabolism in fly brains, we observed that they differently affect the morphology of mitochondria. Our data show that GTPase mutants aggregate mitochondria and inhibit their fusion, whereas, on the contrary, mutations affecting the HB1 domain enhance mitochondrial fusion in motor neurons. This work suggests for the first time that CMT2A could originate from excessive mitochondrial fusion in a significant fraction of patients, and highlights the importance of the tight balance between fusion and fission in neurons.
 
 
 
 

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