TEX44

TEX44 is a testis- and sperm-specific protein that governs assembly of the mitochondrial sheath and structural integrity of the sperm flagellum during spermiogenesis (PMID:40849303, PMID:38750428, PMID:26168773). It acts as a 'mitochondrial glue' by physically interacting with carnitine palmitoyltransferase 1B (CPT1B), anchoring adjacent mitochondria to drive ordered mitochondrial sheath formation along the flagellar midpiece (PMID:40849303). Beyond a structural role, TEX44 directly modulates CPT1B enzymatic activity, restraining conversion of long-chain fatty acids (palmitic and myristic acid) into acyl-carnitines and thereby limiting fatty acid β-oxidation and downstream ROS production (PMID:40849303). Loss of TEX44 in mice unleashes unregulated FAO with excessive ROS, oxidative DNA damage, disorganized 9+2 axonemal microtubule architecture, loss of outer dense fibers, and a malformed midpiece–principal piece junction producing 180° flagellar bending, culminating in defective mitochondrial sheath assembly and male subfertility (PMID:40849303, PMID:38750428, PMID:42133262). Germ-cell-specific Cpt1b deletion phenocopies TEX44 loss, placing CPT1B genetically downstream of TEX44 in this pathway (PMID:40849303).

1. 2015 Medium

   Establishing where TEX44 is expressed was the prerequisite for any functional hypothesis; proteomic and histological detection defined it as a testis/sperm protein.

   Evidence mass spectrometry of human spermatozoa and immunohistochemistry of adult testis

   PMID:26168773

   Open questions at the time

   • no functional role assigned
   • subcellular localization within sperm not resolved
   • no interaction partners identified
2. 2024 High

   Whether TEX44 has a non-redundant role in sperm formation was unknown; complete knockout showed it is required for flagellar architecture during spermiogenesis.

   Evidence CRISPR/Cas9 Tex44-KO mice with electron microscopy and fertility assays

   PMID:38750428

   Open questions at the time

   • molecular mechanism behind structural defects not defined
   • no binding partners identified
   • biochemical activity unknown
3. 2025 High

   The molecular function was resolved by showing TEX44 binds CPT1B as a 'mitochondrial glue' and directly tunes its enzymatic activity, linking flagellar structure to metabolic ROS control.

   Evidence Co-IP and in vitro reconstitution with purified TEX44 and CPT1B, KO mouse ROS/DNA-damage/ultrastructure readouts, and germ-cell-specific Cpt1b conditional KO epistasis

   PMID:40849303

   Open questions at the time

   • structural basis of the TEX44–CPT1B interaction not determined
   • how TEX44 mechanically anchors mitochondria not resolved
   • whether TEX44 regulates additional metabolic enzymes untested
4. 2026 Medium

   Independent KO confirmation with transcriptomics reinforced that TEX44 loss disrupts both 9+2 axonemal organization and mitochondrial sheath assembly programs.

   Evidence CRISPR/Cas9 Tex44-KO mice with CASA, ultrastructural analysis, transcriptomic profiling, and IVF/ICSI assays

   PMID:42133262

   Open questions at the time

   • transcriptomic changes not mechanistically linked to direct TEX44 targets
   • largely confirmatory of prior phenotypes
   • direct cause of axonemal disorganization not established

• The structural mechanism by which TEX44 physically tethers mitochondria and the molecular basis of its modulation of CPT1B remain open.
• no structural model of TEX44 or the TEX44–CPT1B complex
• human disease-causing TEX44 variants not demonstrated
• whether TEX44 has roles outside the mitochondrial sheath unknown