Dysfunctional Mitochondria in the Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model

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.

Automated summary

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a strong cardiovascular phenotype and a distinct neurocognitive profile. The cardiovascular features of WBS are primarily linked to the hemizygosity of the elastin (ELN) gene, but the phenotypic variability suggests the presence of additional modulators. Mitochondrial dysfunction and dynamics have been implicated as potential modulators, and a WBS complete deletion (CD) model exhibits similar mitochondrial phenotypes as observed in WBS patients.