ANKRD5: a key component of the axoneme required for sperm motility and male fertility

Sperm motility is crucial for male reproduction and relies on the structural integrity of the sperm axoneme, which has a “9+2” microtubule configuration. This structure includes nine outer doublet microtubules (DMTs) that house various macromolecular complexes. The nexin-dynein regulatory complex (N-DRC) forms a crossbridge between adjacent DMTs, stabilizing them and facilitates sperm tail bending. Our study of ANKRD5, which is highly expressed in the sperm axoneme, reveals its interaction with DRC5/TCTE1 and DRC4/GAS8, both critical components of the N-DRC, and these interactions were found to be independent of calcium regulation. ANKRD5-/- mice exhibited reduced sperm motility and male infertility. Cryo-electron tomography analysis reveals typical “9+2” axoneme and intact DMT structures in Ankrd5-/- mouse sperm, but the DMTs displayed significant morphological variations and greater structural heterogeneity. Furthermore, ANKRD5 deficiency did not affect ATP level, ROS levels, or mitochondrial membrane potential. These findings suggest that ANKRD5 may weaken the N-DRC’s “car bumper” role, reducing the buffering effect between adjacent DMTs and thereby destabilizing axoneme structures during intense axoneme motility.