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Bioenergetic defect associated with mK ATP channel opening in a mouse model carrying a mitofusin 2 mutation
Author(s) -
Guillet Virginie,
Gueguen Naïg,
Cartoni Romain,
Chevrollier Arnaud,
Desquiret Valérie,
Angebault Claire,
Amati-Bonneau Patrizia,
Procaccio Vincent,
Bonneau Dominique,
Martinou Jean-Claude,
Reynier Pascal
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-173609
Subject(s) - mfn2 , mitochondrion , mitochondrial fusion , mutation , genetically modified mouse , bioenergetics , activator (genetics) , biology , phenotype , transgene , microbiology and biotechnology , gene , chemistry , genetics , mitochondrial dna
Charcot‐Marie‐Tooth disease type 2A (CMT2A) is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene ( MFN2 ), which encodes a mitochon‐drial outer membrane protein that promotes mito‐chondrial fusion. Emerging evidence also points to a role of MFN2 in the regulation of mitochondrial metabolism. To examine whether mitochondrial dysfunction is a feature of CMT2A, we used a transgenic mouse model expressing in neurons a mutated R94Q form of human MFN2 shown to induce a CMT2A phenotype. Oxygraphic and enzymatic measurements both revealed a combined defect of mitochondrial complexes II and V (40 and 30% decrease, respectively) in the brain of Tg‐R94 mice, leading to a drastic decrease of ATP synthesis. These deficiencies were reversed by the mitochondrial ATP‐sensitive potassium channel (mK ATP ) inhibitor 5‐hydroxyde‐canoate. Conversely, in controls and wild‐type human MFN2 mice, the mK ATP activator diazoxide mimicked the deficiency observed with the R94Q mutation. The physical links between complexes II and V, previously proposed as part of mK ATP , were reinforced in Tg‐R94Q mice. Our results show that the R94Q MFN2 mutation induces a combined defect of complexes II and V linked to the opening of mK ATP , which could participate in the pathophysiology of the disease.—Guillet, V., Gueguen, N., Cartoni, R., Chevrollier, A., Desquiret, V., Angebault, C., Amati‐Bonneau, P., Procaccio, V., Bonneau, D., Martinou, J.‐C., Reynier, P. Bioenergetic defect associated with mK ATP channel opening in a mouse model carrying a mitofusin 2 mutation. FASEB J. 25, 1618–1627 (2011). www.fasebj.org