Guillet 2011 FASEB J

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Guillet V, Gueguen N, Cartoni R, Chevrollier A, Desquiret V, Angebault C, Amati-Bonneau P, Procaccio V, Bonneau D, Martinou JC, Reynier P (2011) Bioenergetic defect associated with mKATP channel opening in a mouse model carrying a mitofusin 2 mutation. FASEB J 25:1618-27.

» PMID: 21285398

Guillet V, Gueguen N, Cartoni R, Chevrollier A, Desquiret V, Angebault C, Amati-Bonneau P, Procaccio V, Bonneau D, Martinou JC, Reynier P (2011) FASEB J

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.

Keywords: Charcot-Marie-Tooth type 2A, Succinate dehydrogenase, F0F1-ATP synthase, Mitochondria, Potassium channel

O2k-Network Lab: FR Angers Gueguen N


Labels: MiParea: Respiration, mt-Structure;fission;fusion, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase  Regulation: ADP  Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, Gp, CIV, ROX  HRR: Oxygraph-2k