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

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dc.contributor.authorRamovs, Veronika
dc.contributor.authorChen, Sophia
dc.contributor.authorPatra, Athina
dc.contributor.authorTjokrodirijo, Rayman
dc.contributor.authorVan Veelen, Peter
dc.contributor.authorMulder, Aat
dc.contributor.authorKoning, Roman
dc.contributor.authorStöger, Lauran
dc.contributor.authorHubner, Catalina
dc.contributor.authorIbañez, Rodrigo
dc.contributor.authorMorales, Bernardo
dc.contributor.authorMorandé, Pilar
dc.contributor.authorDell'Oro, Rosario
dc.contributor.authorPoblete, Cristian
dc.contributor.authorSchuster, Andrés
dc.contributor.authorJoao, María
dc.contributor.authorPalisson, Francis
dc.contributor.authorHas, Cristina
dc.contributor.authorJongbloed, Monique
dc.contributor.authorFuentes, Ignacia
dc.contributor.authorMummery, Christine
dc.contributor.authorRaymond, Karine
dc.date.accessioned2026-09-11T16:51:44Z
dc.date.available2026-09-11T16:51:44Z
dc.date.issued2025
dc.description.abstractAims: A striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored. Methods and results: We report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs. Conclusion: The deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.
dc.description.versionVersión Publicada
dc.identifier.citationRamovs, V., Chen, H. S., Patra, A., Tjokrodirijo, R., van Veelen, P., Mulder, A. A., Koning, R. I., Stöger, L., Hubner, C., Ibañez-Arenas, R., Morales Catalan, B., Morandé, P., dell'Oro, R., Poblete, C., Schuster, A., Yubero, M. J., Palisson, F., Has, C., Jongbloed, M., Fuentes, I., … Raymond, K. (2025). KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients. Cardiovascular research, 121(17), 2714–2730. https://doi.org/10.1093/cvr/cvaf231
dc.identifier.doihttps://doi.org/10.1093/cvr/cvaf231
dc.identifier.urihttps://hdl.handle.net/11447/11121
dc.language.isoen
dc.subjectDesmin
dc.subjectDilated cardiomyopathy
dc.subjectKLHL24
dc.subjectSynemin
dc.subjectVimentin
dc.titleKLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceCardiovascular research
dspace.entity.typePublication

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