A new protein isoform encoded by human circular RNA circSLC8a1 contributes to cardiac remodeling

Aims Circular RNA circSLC8a1 has been previously suggested to possess translation potential, but experimental evidence supporting this notion has been lacking. We aim to understand the functions of circSLC8a1 and its translated protein in cardiac remodeling. Methods and Results To elucidate the functional significance of circSLC8a1, we established a transgenic mouse line expressing circSLC8a1 and its translated protein SLC8a1-604. We present compelling evidence confirming the translation potential of circSLC8a1 (hsa_circ_0005232) both in vitro and in vivo. The back-splicing event within hsa_circ_0005232 leads to the generation of a novel circRNA-derived protein comprising 604 amino acids, named SLC8a1-604, which has not been previously reported. These SLC8a1-604 transgenic mice exhibited a heart failure phenotype. In further investigations, we induced pressure overload in the transgenic mice, revealing a significant decrease in heart function compared to litter-matched negative controls. Notably, our findings indicate that the reduced heart function observed in the transgenic mice can be attributed to the presence of the circRNA-translated protein, SLC8a1-604, rather than the circRNA itself. Mechanistically, we found that SLC8a1-604 translocated into mitochondria, where it exerted its effects by binding to POLRMT. This interaction results in a downregulation of mitochondrial gene transcription, leading to a decrease in ATP synthesis. Conclusion Our study provides evidence that circSLC8a1 has the capacity to encode a novel protein isoform, SLC8a1-604, which plays a pivotal role in the regulation of heart functions: circSLC8a1 modulates the remodeling process of cardiac pressure overload by translating into a functional protein. Translational Perspective This proof-of-concept study may lay the foundation for potential clinical applications in circular RNA therapy.