Loss of bves leads to cardiac contractile dysfunction and myocardial mitochondrial damage in zebrafish.

The Popeye domain-containing protein 1 (Popdc1, also known as Bves) is a transmembrane protein whose dysfunction is closely associated with various diseases. Clinical studies have identified that mutations in the bves gene predispose individuals to limb-girdle muscular dystrophy. However, a marked reduction in Bves protein expression has been observed in patients with heart failure, highlighting a critical unresolved challenge in understanding its role in disease pathogenesis. In this study, we discovered that bves deficiency drives cardiac contractile dysfunction, thereby revealing a novel mechanism underlying heart failure pathogenesis. The study found that bves knockout led to cardiac contractile dysfunction in zebrafish during both embryonic and adult stages, with a significant reduction in ejection fraction. Twelve-month-old bves knockout zebrafish exhibited ventricular dilation, increased cardiomyocyte size but significantly decreased cell numbers, and aggravated fibrosis of atrioventricular valves. Transmission electron microscopy revealed widened Z-lines and shortened I-bands in myocardial fibers of the bves knockout group. Collectively, these findings provide compelling evidence that bves knockout induces heart damage. Transcriptome analysis showed disrupted expression of ATP synthesis-related genes and activation of the mitochondrial autophagy pathway following bves knockout. In bves knockout zebrafish, myocardial mitochondria exhibited abnormal structure and impaired oxidative respiratory function, with upregulated expression levels of a series of protein complexes in the mitochondrial electron transport chain. These studies have for the first time established that myocardial mitochondrial structural/functional damage caused by bves deficiency may be associated with the pathogenesis of heart failure, providing a new perspective for the occurrence and development of heart failure.