Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A

Abstract

Mitochondria undergo frequent fusion and fission events, which are essential to maintain a functional mitochondrial network. A disruption of these processes can cause severe neurodegeneration. Charcot-Marie-Tooth disease type 2A (CMT2A) is a neuropathy that is caused by mutations in the fusion factor Mfn2. It is generally assumed that impaired mitochondrial fusion causes CMT2A. However, the detailed molecular mechanism underlying the pathophysiology of CMT2A is only incompletely understood. In this issue of EMBO Reports, El Fissi et al established a fly model to analyze the consequence of frequently occurring MFN2 mutations on locomotor behavior, mitochondrial morphology, and function and find that some pathogenic mutants enhance fusion activity, indicating that increased mitochondrial fusion can drive CMT2A-like pathology [1]. Moreover, this novel assay system will be a useful tool to analyze CMT2A pathogenesis in vivo.

Figure 1. CMT2A pathology in the fly model and mitochondrial fusion activity of the pathogenic alleles

(Left panel) Inhibition of mitochondrial fusion activity in R94Q^like variant leads to aggregation of small mitochondria and impaired locomotor activity. (Middle panel) Appropriate mitochondrial fusion activity in wild‐type fly leads to normal mitochondrial network morphology and locomotor activity. (Right panel) Enhanced mitochondrial fusion activity in the R364W^like variant leads to the formation of enlarged bulb‐like mitochondria and also impaired locomotor activity.