A human mitofusin 2 mutation can cause mitophagic cardiomyopathy.
Level 5 - mechanism / opinion, no new human data
Bench and CRISPR mouse mechanistic study combined with human genetic observational association data.
PubMed 37910431 · doi:10.7554/eLife.84235
What was done
Researchers evaluated the frequency of the rare mitofusin 2 (*MFN2*) R400Q mutation in clinical cardiomyopathy cohorts compared to Charcot-Marie-Tooth disease type 2A (CMT2A). They compared enzymatic GTPase activity, biophysical conformational shifts, Parkin recruitment, mitochondrial motility, and respiration of MFN2 Q400 against wild-type and CMT2A-associated mutants (T105M, M376A/V). They also engineered CRISPR knock-in mice harboring *Mfn2* R400Q, T105M, or M376V, profiling them with RNA sequencing, metabolomics, cardiac phenotyping, and doxorubicin-stress testing in cultured cardiomyoblasts and in vivo cardiomyocytes.
What was found
The *MFN2* R400Q variant was 15–20× over-represented in clinical cardiomyopathy cases. Mechanistically, MFN2 R400Q retained normal catalytic GTPase activity but failed to undergo normal conformational activation and was uniquely defective in recruiting Parkin to mitochondria. Unlike the neuropathic T105M mutant, R400Q did not impair mitochondrial motility, induce depolarization, or suppress basal respiration. *Mfn2* R400Q knock-in mice developed isolated perinatal cardiomyopathy with signature RNA-seq and metabolomic markers of mitophagic failure and heightened sensitivity to doxorubicin, whereas *Mfn2* T105M and M376V knock-in mice showed no cardiac defects.
Why it matters
This study identifies the first natural mitophagy-defective *MFN2* mutation and demonstrates that disruption of cardiac mitochondrial quality control, rather than mitochondrial motility or canonical fusion alone, can cause isolated genetic cardiomyopathy.
Limits
The abstract does not state the human sample size, specific cohort demographics, or exact statistical confidence intervals for the genetic over-representation. Pathophysiological findings rely heavily on mouse knock-in models and in vitro cellular assays, which may not capture the full clinical heterogeneity or modifier landscape in human patients.
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- contradicts The brain has the highest density of mitochondria of any organ in the body.