Dysfunctional Mitochondria in the Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model
Noura Abdalla1, Ester Tobías-Baraja2,3,4, Alejandro Gonzalez1
1Department de Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain.
Insights
Williams-Beuren syndrome (WBS) involves cardiovascular issues linked to elastin gene deficiency. This study shows mitochondrial dysfunction in a WBS mouse model, suggesting it as a therapeutic target for WBS-related heart conditions.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Neurodevelopmental Disorders
Background:
- Williams-Beuren syndrome (WBS) is a rare genetic disorder with significant cardiovascular complications, primarily linked to elastin (ELN) gene hemizygosity.
- Phenotypic variability in WBS suggests other genetic factors modulate the cardiovascular phenotype.
- Mitochondrial dysfunction has been implicated in cardiovascular diseases and recently linked to genes within the WBS region.
Purpose of the Study:
- To investigate mitochondrial function and dynamics in cardiac tissue of a Williams-Beuren syndrome complete deletion (CD) mouse model.
- To determine if mitochondrial dysfunction contributes to the cardiovascular phenotype in WBS.
- To evaluate the utility of the CD mouse model for preclinical testing of mitochondrial-targeted therapies.
Main Methods:
- Analysis of mitochondrial function, including respiratory chain activity and ATP production, in cardiac tissue from CD and wild-type mice.
- Assessment of mitochondrial dynamics through morphological and biochemical analyses.
- Comparison of findings in the CD mouse model with previously observed alterations in WBS patient fibroblasts.
Main Results:
- Cardiac mitochondria from CD animals exhibited altered mitochondrial dynamics.
- A significant decrease in respiratory chain function and ATP production was observed in CD cardiac mitochondria.
- These mitochondrial alterations in the CD model mirror those found in WBS patient-derived fibroblasts.
Conclusions:
- Mitochondrial dysfunction is a likely contributing mechanism to cardiovascular risk factors in Williams-Beuren syndrome.
- The CD mouse model accurately recapitulates the mitochondrial phenotype observed in WBS patients.
- This murine model serves as a valuable platform for preclinical evaluation of drugs targeting mitochondrial dysfunction in WBS.
Abstract:
Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors: on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.
