ReviewRole of mitofusin 2 mutations in the physiopathology of Charcot–Marie–Tooth disease type 2A
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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Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives
2024, Neurobiology of DiseaseRole of tubulin post-translational modifications in peripheral neuropathy
2023, Experimental NeurologyCitation Excerpt :These changes are accompanied by ER stress, Ca2+ handling defects, and changes in the morphology and axonal transport of mitochondria (Bernard-Marissal et al., 2019). Several lines of evidence support a role for perturbation of acetylated tubulin levels in the etiology of CMT2A: 1) MFN2R94Q KO mice, which express a mutated form of human MFN2 (Cartoni and Martinou, 2009) and develop a progressive locomotor impairment and gait defects that mimic CMT2A neuropathic symptoms in humans, are reported to lack of acetylated tubulin in distal axons of their long peripheral nerves (Cartoni et al., 2010; Picci et al., 2020); 2) HDAC6 inhibition has been shown to be a promising therapeutical approach in several toxic and familial PNs including CMT2A while restoring defects in axonal transport (Benoy et al., 2015; Benoy et al., 2016; d'Ydewalle et al., 2011); 3) the formin INF2, causative of dominant intermediate CMT in association with focal segmental glomerulosclerosis (FSGS) when mutated (Boyer et al., 2011), is a positive regulator of tubulin acetylation by modulating ATAT1 mRNA transcription (Fernandez-Barrera et al., 2018), suggesting that targeting tubulin acetylation may represent a successful therapeutic approach aimed at restoring sensory neuron function in CMT2A and related neuropathies. A decrease in the level of tubulin acetylation in sensory neurons is also reported in the Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) mouse model (Lynch-Godrei et al., 2018).
Peripheral neuropathy in mitochondrial disease
2023, Handbook of Clinical NeurologyPharmacological advances in mitochondrial therapy
2021, EBioMedicineCitation Excerpt :Mitochondrial dynamics is an essential physiological process that,through coordinated fusion and fission events, orchestrates proper intracellular positioning of mitochondria at areas of high-energy requirements [80]. Alterations in mitochondrial dynamics are associated with cancer development and progression of cardiovascular and neurodegenerative conditions [81,82], besides representing a causative event in some mitochondria-related neuropathies, such as Charcot-Marie-Tooth type 2 subtype A (CMT2A) and autosomal dominant optic atrophy (ADOA) [83,84]. There is therefore a growing interest in the development of compounds to restore mitochondrial dynamics.
Genetic mechanisms of peripheral nerve disease
2021, Neuroscience Letters