KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients.

Summary

Across patient heart tissue and patient-specific hiPSC-derived cardiomyocytes, KLHL24 gain-of-function drives proteasome-dependent degradation of multiple intermediate filament proteins, mitochondrial mislocalization with enhanced mitophagy, reduced PKA activity, sarcomere shortening, and an early fibrotic signature. These convergent data establish a unifying mechanism for cardiomyopathy in KLHL24 mutation carriers.

Key Findings

• Proteomics in patient LV tissue and patient-derived hiPSC-CMs showed reductions in multiple intermediate filament proteins (desmin, synemin, vimentin) and early fibrotic signatures.
• KLHL24 gain-of-function increased proteasomal activity, caused mitochondrial mislocalization with elevated mitophagy, reduced PKA activity, and induced sarcomere shortening in cardiomyocytes.
• Phenotypes were reproduced across cardiac cell types, including cardiomyocytes and fibroblasts, and aligned between in vitro models and end-stage explants.

Clinical Implications

Genetic screening for KLHL24 variants in epidermolysis bullosa and unexplained cardiomyopathy may be warranted; therapeutic exploration could include proteasome modulation, stabilization of intermediate filaments, or mitochondrial protection strategies.

Limitations

• Human cohort limited to two patients; lack of in vivo rescue experiments or therapeutic modulation
• hiPSC models may not capture hemodynamic and multicellular tissue architecture present in vivo

Future Directions

Define the KLHL24 substrate landscape, test proteostasis and mitochondrial-targeted therapies in preclinical models, and expand clinical cohorts to link genotype, proteomic signatures, and phenotype severity.