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Excessive intermediate filament degradation and mitochondrial changes in heart failure patients carrying KLHL24 gain-of-function mutation

ABSTRACT: A striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening heart deterioration. The encoded protein, KLHL24, belongs to the ubiquitin-proteasome system that regulates protein turnover, acting as a substrate-specific adaptor protein to E3 ubiquitin ligase. It is thought that KLHL24mut is a gain-of-function mutation and associated cardiac and skin pathologies stem from excessive degradation of KLHL24mut target proteins. Thus far, all reported targets of KLHL24mut belong to the intermediate filament protein family and a reduction of desmin in cardiomyocytes is the only reported mechanism of KLHL24mut-driven heart pathology. In this study we investigate the cardiac phenotype driven by KLHL24mut and its underlying mechanism by combining clinical patient data with proteomic analysis. Using human induced pluripotent stem cell-derived cardiac models and patient cardiac tissue we demonstrate that KLHL24mut leads to defects in mitochondria, muscle fibers and intermediate filament proteins. Our study shows that KHL24mut affects multiple cardiac cell types and has numerous downstream targets, notably synemin and desmin in cardiomyocytes and vimentin in cardiac fibroblasts. Thus, KLHL24mut can affect several proteins in multiple types of cells, underscoring the need for a holistic approach when designing diagnosis, treatment, and research models tackling this disease.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Cell Culture

SUBMITTER: Rayman Tjokrodirijo

LAB HEAD: Peter A. van Veelen

PROVIDER: PXD051917 | Pride | 2025-12-03

REPOSITORIES: Pride

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Project description:Background: Mutations of the desmin gene cause familial and sporadic cardiomyopathies and myopathies. Previous studies showed that both the lack of desmin and expression of mutated desmin negatively impact on number, structure and function mitochondria implying a metabolic dysfunction as disease promoting factor. Here, we exploited desmin knock-out mice to analyse the general metabolic performance of cardiac tissue. Methods: We analysed left ventricular cardiac muscle tissue derived from six-month-old homozygous desmin knock-out mice as well as wild-type siblings. Employing a multi-method approach comprising morphological, clinical chemistry, biochemical, genetic, and proteomic techniques, we specifically addressed energy, fatty acid, glucose, and amino acid metabolism. Results: We demonstrated that the lack of desmin in left ventricular cardiac tissue led to a significant decrease in the number of mitochondria in conjunction with ultrastructural defects of mitochondria. Analysis of mitochondria-related metabolic pathways revealed significantly impaired processes of fatty acid transport, activation, and catabolism associated with increased blood levels of short, medium, and long chain acyl-carnitines. In addition to increased amounts of glucose transporter 1 and hexokinase 1, we detected a significantly increased hexokinase enzyme activity. While the amount of mitochondrial creatine kinase was markedly reduced, fetal creatine kinase was increased. The picture of a highly dysbalanced metabolic state was complemented by our quantitative proteomic analysis that revealed significantly reduced levels of multiple proteins centrally involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Conclusions: Our data denoted a picture of widespread metabolic dysfunction far reaching beyond the level of mitochondria in left ventricular cardiac tissue of desmin knock-out mice. The increase of glucose utilisation along with increased level of fetal creatine kinase likely is a compensatory measure counteracting the severely hampered fatty acid metabolism and oxidative phosphorylation. The degree of metabolic disbalance, already observed in desmin knock-out mice kept under standard ‘sedentary’ housing conditions, renders it likely that acute strenuous physical exercise with its steeply increased energy demand will push the cardiac tissue into severe metabolic crisis.

			Action	DRS
	Control_sample_WT1.msf	Msf
	Control_sample_WT2.msf	Msf
	E20232000290a.raw	Raw
	E20232000291a.raw	Raw
	E20232000292a.raw	Raw

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Excessive intermediate filament degradation and mitochondrial changes in heart failure patients carrying KLHL24 gain-of-function mutation

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