Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Antonietta Franco; Xiawei Dang; Emily K Walton; Joshua N Ho; Barbara Zablocka; Cindy Ly; Timothy M Miller; Robert H Baloh; Michael E Shy; Andrew S Yoo; Gerald W Dorn II

doi:10.7554/eLife.61119

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Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Journal article

Open access

Peer reviewed

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Antonietta Franco, Xiawei Dang, Emily K Walton, Joshua N Ho, Barbara Zablocka, Cindy Ly, Timothy M Miller, Robert H Baloh, Michael E Shy, Andrew S Yoo, …

eLife, Vol.9, e61119

10/19/2020

DOI: 10.7554/eLife.61119

PMCID: PMC7655101

PMID: 33074106

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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 mutation. In mice expressing human 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 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.

Motor Neurons - physiology

Neuromuscular Junction - metabolism

Mice, Inbred C57BL

Mitochondria, Muscle - metabolism

Muscle Cells - metabolism

Axons - metabolism

Male

Axons - physiology

Mitochondrial Proteins - genetics

Mutation - genetics

Motor Neurons - metabolism

Muscle Cells - physiology

Animals

GTP Phosphohydrolases - metabolism

GTP Phosphohydrolases - genetics

Mitochondrial Proteins - metabolism

Mitochondria, Muscle - physiology

Female

Mice

Charcot-Marie-Tooth Disease - physiopathology

Charcot-Marie-Tooth Disease - metabolism

Neuromuscular Junction - physiology

Details

Title: Subtitle: Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A
Creators: Antonietta Franco - Department of Internal Medicine, Pharmacogenomics, Washington University School of Medicine, St Louis, United States
Xiawei Dang - Department of Cardiology, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
Emily K Walton - Department of Internal Medicine, Pharmacogenomics, Washington University School of Medicine, St Louis, United States
Joshua N Ho - Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, United States
Barbara Zablocka - Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Cindy Ly - Department of Neurology, Washington University School of Medicine, St Louis, United States
Timothy M Miller - Department of Neurology, Washington University School of Medicine, St Louis, United States
Robert H Baloh - Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, United States
Michael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, United States
Andrew S Yoo - Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, United States
Gerald W Dorn II - Department of Internal Medicine, Pharmacogenomics, Washington University School of Medicine, St Louis, United States
Resource Type: Journal article
Publication Details: eLife, Vol.9, e61119
DOI: 10.7554/eLife.61119
PMID: 33074106
PMCID: PMC7655101
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: England
Grant note: R41 NS115184 / NINDS NIH HHS U54 NS053672 / NINDS NIH HHS 628906 / Muscular Dystrophy Association R35 HL135736 / NHLBI NIH HHS U54 NS065712 / NINDS NIH HHS R41 NS113642 / NINDS NIH HHS
Language: English
Date published: 10/19/2020
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984070835002771

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