Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A
- Washington University School of Medicine, United States
- Mossakowski Medical Research Centre, Poland
- Cedars-Sinai Medical Center, United States
- Carver College of Medicine, University of Iowa, United States
Abstract
Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.
Data availability
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Author details
Funding
NIH (R35HL135736)
- Gerald W Dorn II
NIH (R41NS113642)
- Gerald W Dorn II
NIH (R41NS115184)
- Gerald W Dorn II
Muscular Dystrophy Association (628906)
- Gerald W Dorn II
McDonnell Center for Cellular and Molecular (Neurobiology Postdoctoral Fellowship)
- Antonietta Franco
Harrington Discovery Institute (Scholar-Innovator awardee)
- Gerald W Dorn II
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental procedures were approved by Washington University in St. Louis School of Medicine Animal Studies Committee; IACUC protocol number 19-0910, Exp:12/16/2022 (Gerald Dorn, PI).
Copyright
© 2020, Franco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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