A novel CCDC112-dependent process of sperm midpiece formation and epididymal maturation

Abstract The sperm mitochondrial sheath has proposed functions in structural support and energy production for motility. Here we define coiled coil domain containing protein 112, CCDC112, as crucial for male fertility, specifically in the assembly and function of the mitochondrial sheath. We unveiled a previously unrecognised process of epididymal mitochondrial sheath maturation. Sperm mitochondrial sheaths are structurally immature upon exiting the testis and continue to mature as they transit from the caput to the cauda epididymis. Data reveal the critical role of CCDC112 in mitochondrial morphogenesis during sheath formation. A lack of CCDC112 lead to significantly reduced mitochondrial respiration capacity, irregular flagellar waveforms, diminished progressive motility and a failure of sperm to traverse the female reproductive tract to the site of fertilisation and penetrate the zonae pellucidae of oocytes. Finally, we identify CCDC112 as a component of the distal appendages of the mother centriole and identify a facilitative role in core tail assembly. Collectively, CCDC112 is a key regulator of sperm mitochondrial sheath assembly while further expanding the understanding of spermatogenesis, energy generation and flagella kinematics.