Faculty, Staff and Student Publications
Publication Date
11-1-2023
Journal
eLife
Abstract
Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse
Keywords
Pregnancy, Female, Humans, Mice, Animals, Membrane Proteins, Mitochondrial Proteins, Mutation, GTP Phosphohydrolases, Cardiomyopathies, Charcot-Marie-Tooth Disease
DOI
10.7554/eLife.84235
PMID
37910431
PMCID
PMC10619978
PubMedCentral® Posted Date
11-1-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes