Review articleMFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives
Introduction
Mitochondria are highly dynamic cytosolic organelles that play a fundamental role in eukaryotic cells by providing the ATP required for metabolic processes via oxidative phosphorylation [1]. Moreover, mitochondria are involved in several other metabolic pathways, including those for the Krebs cycle, fatty acid metabolism, gluconeogenesis and heme-synthesis. In addition, mitochondria regulate intracellular calcium signaling and apoptosis [2]. Mitochondria are present in all cells of the body (except for erythrocytes) and are enriched in neurons, especially within the presynaptic and postsynaptic terminals [3] and within the nodes of Ranvier [4], because of the high energetic demand and calcium flux within these neuronal regions. Mitochondrial dynamics subserve a complex machinery of highly conserved mechanisms, such as mitochondrial fusion and fission, short- and long-distance transport (i.e. “mitochondrial trafficking”), interorganellar communication and mitochondrial quality control (i.e. mitophagy). All these processes are skillfully orchestrated by a considerable number of intracellular proteins including mitofusin 2 (MFN2) [3]. Moreover, these processes interact and influence each other to maintain cellular bioenergetics and the ability to respond to stress [5]. Notably, neurons, more than other cell type, strongly depend on such mitochondrial dynamics [6]. Indeed, the relationship between mitochondria and neurons is essential for neuronal function and it is reasonable to suggest that defective mitochondrial physiology may lead to neurodegeneration [7], [8], [9]. Accordingly, a growing number of studies suggest that impaired mitochondrial dynamics, deficiency in mitochondrial quality control and perturbed mitochondrial trafficking likely contribute to the causative mechanisms of several neurodegenerative pathologies, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD) [3], [9], [10], [11], [12], [13]. MFN2 is a key protein for mitochondrial function, involved not only in mitochondrial fusion but also in several mitochondrial dynamics, such as trafficking and mitophagy. In the presence of MFN2 mutations, the mitochondrial functional network is impaired [14], [15], [16]. MFN2 mutations are linked to neurological disorders, such as hereditary neuropathies and more complex neurological phenotypes. In this context, the analysis of the MFN2-related disorders can be useful to elucidate the mechanisms through which mitochondrial impairment likely contributes to neurological dysfunction and neurodegeneration [1]. Moreover, additional knowledge of the pathogenic role of mitochondrial defects may identify novel therapeutic targets for orphan neurological diseases.
Here, we report the broad clinical spectrum and genetic background of MFN2-related disorders. We also review proposed pathogenic mechanisms through which the MFN2 alterations likely impair mitochondrial function in neurons. In addition, we present potential therapeutic approaches for the neurological diseases linked to MFN2 mutations.
Section snippets
Clinical features of MFN2-related disorders
The mitofusin 2 (MFN2) gene mutations are associated with Charcot–Marie–Tooth (CMT) disease-2A, which is a neurological disorder that presents complex phenotypes, including not only neuropathy-related features but also systemic impairment of the central nervous system (CNS) [17], [18]. CMT2A is the most frequent axonal form of CMT, accounting for approximately 20% of the diagnosed cases [19]. Clinically, the classic form of CMT2A is characterized by physical weakness, foot deformities (pes
Genetic background of MFN2-related neuropathies
In 2004, Züchner et al. first identified a heterozygous mutation in the MFN2 gene (281G-A transition), resulting in a R94Q substitution in the predicted beginning of the GTPase domain of the protein in CMT2A-affected members described by Saito [37].
To date, more than 100 CMT2A disease-causing mutations have been described for the MFN2 gene, and these mutations are preferentially located within the GTPase domain and in the downstream region before the HR1 domain [38]. The amino acid residue of
MFN2 role on the mitochondrial network
MFN2 is a key protein that maintains cellular bioenergetics by orchestrating the mitochondrial functional network [3], [5], which is a complex machinery of highly conserved mechanisms that includes mitochondrial fusion and fission, trafficking, interorganellar communication between mitochondria and the endoplasmic reticulum (ER) and mitophagy) [45]. MFN2 not only has a mitochondria-shaping function, but also plays an essential role in almost all mitochondrial dynamics, including regulating the
Therapeutic perspectives
Currently, there is no known effective disease-modifying treatment for MFN2-related disorders. For CMT neuropathies, supportive care includes exercise, physical and occupational therapy and orthotics designed to address foot drop symptoms and to stabilize gait; analgesic agents are used for neuropathic and mechanical pain; and surgery intended to maintain function of the distal lower limbs is available [84], [85]. Systematic studies on the effect of orthotics on gait in CMT are relatively
Conclusions
Previous studies suggest that MFN2 is involved in several intracellular pathways that interact to regulate the mitochondrial network within cells, especially neurons. Complex MFN2 molecular and cellular dynamics may account for the broad clinical features of CMT2A, which are also likely influenced by environmental and epigenetic factors. This complexity of pathogenic interactions makes it difficult to treat this type of disorder. To date, no effective therapies are available for MFN2-related
Conflict of interest
No conflict of interest.
Funding
Financial support from PROGETTO MITOFUSINA 2 ONLUS Association is gratefully acknowledged.
Acknowledgments
We wish to thank the Associazione Amici del Centro Dino Ferrari for their support.
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