Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

CCDC112 is essential for the novel process of sperm mitochondrial sheath maturation and male fertility in the mouse (#8)

Maddison L Graffeo 1 , Farin Yazdan Parast 2 , Jessica EM Dunleavy 1 , Joseph Nguyen 1 , Denis Korneev 2 , Hidenobu Okuda 3 , Anne E O'Connor 1 , Don F Conrad 4 , Reza Nosrati 2 , Brendan Houston 1 , Moira O'Bryan 1
  1. University of Melbourne, Parkville, VIC, Australia
  2. Monash University, Clayton, VIC, Australia
  3. Moriguchi Keijinkai Hospital, Osaka, Japan
  4. Oregon Health & Science University, Beaverton, Oregon

The mitochondrial sheath is a key requirement for sperm function, providing structural support and energy to the midpiece that is necessary for flagella movement (1-7). While many key steps in sperm midpiece formation have been described, the molecular processes required for its assembly and function remain poorly understood. Recent findings suggest a core role for the coiled coil domain containing 112 protein, CCDC112, in cilia/flagella formation (8, 9).  Using a Ccdc112 knockout mouse model, we examined the function of CCDC112 during spermatogenesis, particularly in sperm flagellum formation. Our data identified that CCDC112 is required for normal sperm structure and motility and male fertility. Remarkably, we also unveiled a previously unrecognised process of mitochondrial sheath maturation that occurs outside the testis during epididymal sperm transit. Using a novel scanning electron microscopy and sperm membrane stripping approach, we have shown that sperm midpieces are structurally immature upon exiting the testis and that maturation continues as sperm transit from the caput to the cauda epididymis. Our data further reveal that CCDC112 is enriched in haploid male germ cells and that it plays a critical role in mitochondrial morphogenesis and remodelling during mitochondrial sheath formation. The loss of CCDC112 resulted in sperm with highly abnormal mitochondrial sheath architecture, stiff and inflexible midpieces and significantly reduced mitochondrial respiration capacity. Consequently, Ccdc112 null sperm possessed an irregular flagellar waveform and harboured significant reductions in mechanical power, causing a 26% reduction in swimming speed and a 69% reduction in progressive motility. Ultimately, Ccdc112 null sperm are unable to traverse the female reproductive tract to the site of fertilisation and were incapable of successfully penetrating the oocyte, in vitro. Collectively, we reveal a novel form of epididymal sperm maturation and show that CCDC112 is essential for male fertility as a key regulator of sperm midpiece assembly and function.

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