Heart failure & cardiomyopathies
Disruption of cTnT-Mediated Sarcomere–Mitochondrial Communication Results in Dilated Cardiomyopathy
Authors' conclusion
Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere-mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein-mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis.
Study context
- Population
- Dilated cardiomyopathy (DCM) family cohort carrying cTnT (p.K185E) variant; iPSC-derived cardiomyocytes and organoids; knock-in mice (p.K192E)familial DCM cohort
Methodological detailsiPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, CRISPR-Cas9 corrected isogenic induced pluripotent stem cells (iPSCs), knock-in mouse model, RNA sequencing, metabolite profiling and coimmunoprecipitation mass spectrometry
- iPSC-derived cardiomyocytes
- iPSC-derived cardiac organoids
- CRISPR-Cas9 corrected isogenic iPSCs
- Knock-in mouse model
- RNA sequencing, metabolite profiling and coimmunoprecipitation mass spectrometry
Main finding
As reported in the abstract
- Novel pathogenic cTnT variant (p.K185E) identified by whole exome sequencing as causal in familial DCM
- Patient iPSC-derived cardiomyocytes: sarcomere disarray, mitochondrial fragmentation, severe mitochondrial dysfunction
- Diminished cTnT (p.K185E)–14-3-3 interaction, with dissociation of 14-3-3 from sarcomeres
- Free 14-3-3 engaged RAS/RAF1 axis, driving aberrant p44/42 activation and phosphorylation of DRP1 and MFF
- Findings replicated in iPSC-derived cardiac organoids
- Knock-in mice recapitulated DCM: cardiac dysfunction, ventricular dilatation, sarcomeric disarray, mitochondrial fragmentation
- Mdivi-1 (mitochondrial fission inhibitor) alleviated DCM phenotypes in vivo
Original publication
Disruption of cTnT-Mediated Sarcomere–Mitochondrial Communication Results in Dilated Cardiomyopathy. Circulation. Published 27 May 2025. doi:10.
Summarised from the published abstract; every number is checked against it