A novel protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis

BackgroundCircular RNAs (circRNAs) are a large class of mammalian RNAs. Several protein products translated by circRNAs have been reported to be involved in the development of various tissues and systems; however, their physiological functions in male reproduction have yet not been explored.ResultsHere, we report an endogenous circRNA (circRsrc1) that encodes a novel 161-amino-acid protein which we named Rsrc1-161aa through circRNA sequencing coupled with mass spectrometry analysis on mouse testicular tissues. Deletion of Rsrc1-161aa in mice impaired male fertility with a significant decrease in sperm count and motility due to dysfunctions of mitochondrial energy metabolism. A series of in vitro rescue experiments revealed that circRsrc1 regulates mitochondrial functions via its encoded protein Rsrc1-161aa. Mechanistically, Rsrc1-161aa directly interacts with mitochondrial protein C1qbp and enhances its binding activity to mitochondrial mRNAs, thereby regulating the assembly of mitochondrial ribosomes and affecting the translation of oxidative phosphorylation (OXPHOS) proteins and mitochondrial energy metabolism.ConclusionsOur studies reveal that Rsrc1-161aa protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis, thereby affecting male fertility.

Automated summary

In this study, an endogenous circular RNA (circRsrc1) was discovered, which encodes a novel protein (Rsrc1-161aa). Deletion of Rsrc1-161aa in mice resulted in impaired male fertility, characterized by decreased sperm count and motility due to mitochondrial energy metabolism dysfunctions. In vitro experiments showed that circRsrc1 regulates mitochondrial functions through its encoded protein Rsrc1-161aa. Mechanistically, Rsrc1-161aa interacts with mitochondrial protein C1qbp to enhance its binding activity to mitochondrial mRNAs, thereby regulating mitochondrial ribosome assembly and translation.