Finding a new balance to cure Charcot-Marie-Tooth 2A
Keiko Iwata, Luca Scorrano
Keiko Iwata, Luca Scorrano
Published April 1, 2019; First published March 18, 2019
Citation Information: J Clin Invest. 2019;129(4):1533-1535. https://doi.org/10.1172/JCI127820.
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Commentary

Finding a new balance to cure Charcot-Marie-Tooth 2A

Abstract

Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strategy for CMT2A.

Authors

Keiko Iwata, Luca Scorrano

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Figure 1

The MFN-mediated fusion models.

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The MFN-mediated fusion models. (A) Schematic of the MFN2 protein. MFN2 ...
(A) Schematic of the MFN2 protein. MFN2 is embedded in the OMM by a TM and is composed of a GTPase domain and heptad repeat domains (HR1 and HR2). IMM, inner mitochondrial membrane. (B) MFN2 interacts in trans forming either homotypic or heterotypic (with MFN1) dimers to produce the mitochondrial tethering that precedes mitochondrial fusion. (C) MFNs may dimerize in trans upon GTP binding, which leads to long-distance docking of mitochondria. GTP hydrolysis can then induce a large conformational rearrangement of MFNs that brings OMMs into closer proximity. Mitochondrial fusion proceeds as a result of local membrane deformation near the TM domain when MFNs undergo GTP hydrolysis–dependent conformational transition and membrane structure perturbation by the HR1 domain (asterisks). (D) Schematic depiction of the folded (with HR2 constrained; left) and unfolded (with HR2 extended; right) MFN conformations. HR2 unfolding is below.