Elsevier

Experimental Neurology

Volume 218, Issue 2, August 2009, Pages 268-273
Experimental Neurology

Review
Role of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A

https://doi.org/10.1016/j.expneurol.2009.05.003Get rights and content

Abstract

Charcot–Marie–Tooth disease (CMT) is the most common form of hereditary peripheral neuropathy. The main axonal form of CMT, CMT2A, preferentially affects peripheral neurons with the longest neurites. CMT2A has been recently linked to mutations in the mitofusin 2 (Mfn2) gene. Mfn2 participates in mitochondrial fusion a process that together with mitochondrial fission, contributes to mitochondrial morphology. Many hypotheses have been postulated to understand how mutations in Mfn2 lead to CMT2A. In this review, we will describe the physiological role of Mfn2, the pathophysiology of CMT2A and current hypotheses about the deleterious role of mutant Mfn2 in neuronal function.

Section snippets

Charcot–Marie–Tooth disease type 2A

Charcot–Marie–Tooth (CMT) disease (also known as hereditary motor and sensory neuropathy) represents a group of clinically and genetically heterogeneous inherited neuropathies affecting motor and/or sensory neurons and associated Schwann cells. It has been first described independently in France and Great Britain at the end of the 19th century (Charcot and Marie, 1886, Tooth, 1886). The CMT disease is the most common inherited neuromuscular disorder with a prevalence estimated at 1/2500 (Skre,

Mitofusins and mitochondrial fusion

Mitochondria are not isolated organelles but rather form highly dynamic structures that continuously fuse and fragment. Together with Mfn1 and OPA1, Mfn2 plays a major role in the mitochondrial fusion process in mammalian cells (for review see Chan, 2006). The first mitochondrial fusion protein called Fzo has been described in Drosophila (Hales and Fuller, 1997). Mutants for the Fzo protein displayed sterility due to abnormal mitochondrial fusion in the spermatids. Instead of the classical

CMT2A due to mitochondrial fusion impairment

Knock down of mitofusins 1, 2 and OPA1, three proteins involved in mitochondrial fusion, has a considerable impact on mouse development. Mitofusin1 and 2 deficient mice are unviable. They die at embryonic day 12.5 and 11.5, respectively. Mfn2 KO lethality is due to a fatal defect of the giant cell layer of the placenta, which is less abundant and contain smaller nuclei than normal (Chen et al., 2003). Notably, no defect in placental development was reported for the Mfn1 KO embryos. Recently,

Mfn2 and cell bioenergetics

The implication of Mfn2 in cell bioenergetics was first proposed by Zorzano et al. They reported that a down-regulation of Mfn2 in L6E9 myotubes induced a reduction in glucose oxidation and mitochondrial membrane potential (Bach et al., 2003). They further showed a down-regulation of Mfn2 mRNA and protein in skeletal muscles of obese Zucker rats and patients. Still in human skeletal muscles, Mfn2 expression has been shown to be up-regulated after acute exercise (Cartoni et al., 2005).

Mfn2-induced CMT2A: a mitochondrial transport disorder

Mitochondrial transport and distribution are particularly crucial for neurons. Because of their polarity with long axons and dendrites, high energy levels are often required far from the soma, for example at synapse levels. This is possible thanks to mitochondria. Current models propose that a mitochondrial transport defect could be the cause of CMT2A. Zhao et al. (2001) were the first to link axonal cargo transport dysfunction to CMT2A. They characterized KIF1Bβ as a new isoform of the

Perspectives and conclusions

CMT2A peripheral neuropathy is an invalidating disease affecting approximately 40,000 people in the US. Major advancement in our understanding of this disease has been made with the identification of Mfn2 mutations in a substantial set of CMT2A patients. So far there is no treatment available for this disease. Over the last recent years we have learnt a lot about the mechanism of action of Mfn2 and its implication in the disease. The generation of an animal model of the disease should be useful

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