Bioenergetic defect associated with mKATP channel opening in a mouse model carrying a mitofusin 2 mutation.

نویسندگان

  • Virginie Guillet
  • Naïg Gueguen
  • Romain Cartoni
  • Arnaud Chevrollier
  • Valérie Desquiret
  • Claire Angebault
  • Patrizia Amati-Bonneau
  • Vincent Procaccio
  • Dominique Bonneau
  • Jean-Claude Martinou
  • Pascal Reynier
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Mitochondrial potassium ATP channels and retinal ischemic preconditioning.

PURPOSE To examine the mechanisms of ischemic preconditioning (IPC) related to the opening of mitochondrial KATP (mKATP) channels in the retina. METHODS Rats were subjected to retinal ischemia after IPC, or retinas were rendered ischemic after pharmacological opening of mKATP channels. The effects of blocking mKATP channel opening, nitric oxide synthase (NOS) subtypes, or protein kinase C (PK...

متن کامل

KATP channel openers have opposite effects on mitochondrial respiration under different energetic conditions.

Mitochondrial (m) KATP channel opening has been implicated in triggering cardiac preconditioning. Its consequence on mitochondrial respiration, however, remains unclear. We investigated the effects of two different KATP channel openers and antagonists on mitochondrial respiration under two different energetic conditions. Oxygen consumption was measured for complex I (pyruvate/malate) or complex...

متن کامل

Accelerated Recovery of Mitochondrial Membrane Potential by GSK-3β Inactivation Affords Cardiomyocytes Protection from Oxidant-Induced Necrosis

Loss of mitochondrial membrane potential (ΔΨm) is known to be closely linked to cell death by various insults. However, whether acceleration of the ΔΨm recovery process prevents cell necrosis remains unclear. Here we examined the hypothesis that facilitated recovery of ΔΨm contributes to cytoprotection afforded by activation of the mitochondrial ATP-sensitive K+ (mKATP) channel or inactivation ...

متن کامل

Buckling Behavior of Composite Plates with a Pre-central Circular Delamination Defect under in-Plane Uniaxial Compression

Delamination is one of the most common failure modes in composite structures. In the case of in-plane compressional loading, delamination of a layered flat structure can cause a local buckling in delaminated area which subsequently affects the overall stiffness of the initial structure. This leads to an early failure of the overall structure. Moreover, with an increase in load, the delaminated ...

متن کامل

Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning.

ATP-sensitive K(+) (KATP) channels that contain K(+) inward rectifier subunits of the 6.2 isotype (Kir6.2) are important regulators of the cardiac response to ischemia-reperfusion (I/R) injury. Opening of these channels is implicated in the cardioprotective mechanism of ischemic preconditioning (IPC), but debate surrounds the contribution of surface KATP (sKATP) versus mitochondrial KATP (mKATP...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • FASEB journal : official publication of the Federation of American Societies for Experimental Biology

دوره 25 5  شماره 

صفحات  -

تاریخ انتشار 2011