TEX44 CPT1B Axis Regulates Mitochondrial Sheath Assembly and Fatty Acid Oxidation in Sperm

Mitochondrial fatty acid β-oxidation (FAO) is critical for cellular energy homeostasis, yet its regulatory role in sperm remains elusive. Whole-exome sequencing of 800 asthenozoospermia patients revealed biallelic TEX44 mutations in six individuals with defective mitochondrial sheath assembly and impaired motility. In Tex44 knockout mice, TEX44 interacts with CPT1B to form a mitochondrial "glue," securing adjacent mitochondria and enabling sheath formation. In vitro, TEX44 directly suppresses CPT1B-mediated conversion of palmitic/myristic acid to acyl-carnitines, curbing reactive oxygen species (ROS) production. TEX44 deficiency disrupts this control, triggering uncontrolled FAO, ROS overaccumulation, and oxidative damage to sperm DNA and flagella. Germ cell-specific Cpt1b knockout mice mirrored these phenotypes, confirming the TEX44-CPT1B axis's functional synergy. Our study uncovers a sperm-specific regulatory axis wherein TEX44 balances CPT1B activity to coordinate mitochondrial sheath biogenesis and FAO restraint, thereby preserving genomic integrity and motility. These findings illuminate mechanistic links between energy metabolism dysregulation, mitochondrial ultrastructure defects, and male infertility.