TEX44

TEX44 is a testis-expressed mitochondrial sheath protein essential for sperm flagellum assembly and male fertility. It physically interacts with carnitine palmitoyltransferase 1B (CPT1B) to form an intermitochondrial glue that anchors adjacent mitochondria during mitochondrial sheath biogenesis in spermiogenesis (PMID:40849303). TEX44 directly modulates CPT1B enzymatic activity, limiting long-chain fatty acid β-oxidation and thereby restraining reactive oxygen species production; loss of TEX44 causes unregulated β-oxidation, excessive ROS, oxidative damage to sperm DNA and flagella, disorganized midpiece–principal piece junctions, loss of axonemal microtubule doublets and outer dense fibers, and severe male subfertility (PMID:40849303, PMID:38750428).

1. 2024 High

   Whether TEX44 is required for sperm flagellum formation was unknown; gene deletion revealed that TEX44 is essential for correct assembly of the midpiece–principal piece junction, maintenance of axonemal doublets and outer dense fibers, and sperm motility.

   Evidence CRISPR/Cas9 complete Tex44 gene deletion in mice with transmission electron microscopy and motility assays

   PMID:38750428

   Open questions at the time

   • Molecular binding partners mediating TEX44's structural role were unidentified
   • Whether flagellar defects reflect a primary mitochondrial sheath defect or an independent cytoskeletal role was unresolved
   • No enzymatic or metabolic function had been attributed to TEX44
2. 2025 High

   How TEX44 organizes the mitochondrial sheath was resolved: TEX44 binds CPT1B to glue adjacent mitochondria together, and simultaneously limits CPT1B-mediated long-chain fatty acid β-oxidation to prevent excessive ROS; germ cell-specific Cpt1b knockout phenocopies Tex44 loss, confirming they operate in the same pathway.

   Evidence Co-immunoprecipitation, in vitro enzymatic reconstitution with purified TEX44, Tex44 KO and conditional Cpt1b KO mice with ROS and oxidative damage readouts

   PMID:40849303

   Open questions at the time

   • Structural basis of the TEX44–CPT1B interaction (binding interface, stoichiometry) is undefined
   • Whether TEX44 has additional mitochondrial partners beyond CPT1B is unknown
   • Whether human TEX44 mutations cause male infertility has not been demonstrated

• Key open questions include the atomic-level mechanism by which TEX44 inhibits CPT1B catalysis, whether TEX44 has roles outside spermiogenesis, and whether TEX44 variants are causative in human asthenozoospermia or multiple morphological abnormalities of the sperm flagella (MMAF).
• No structural model of the TEX44–CPT1B complex exists
• No human genetic studies linking TEX44 mutations to infertility have been reported
• Regulation of TEX44 expression and protein turnover during spermiogenesis is uncharacterized