CMT 2A: Bioenergetic defect associated with mKATP channel opening in a mouse mod

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FASEB J. 2011 Feb 1

Bioenergetic defect associated with mKATP channel opening in a mouse model

carrying a mitofusin 2 mutation.

Guillet V, Gueguen N, Cartoni R, Chevrollier A, Desquiret V, Angebault C,

Amati-Bonneau P, Procaccio V, Bonneau D, ou JC, Reynier P.

*Unité Mixte de Recherche (UMR) Centre National de la Recherche Scientifique

(CNRS) 6214, Institut National de la Santé et de la Recherche Médicale (INSERM)

U771, Angers, France

Abstract

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 mitochondrial outer membrane protein that promotes mitochondrial

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-hydroxydecanoate. 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.