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<p>Mitochondrial fatty acid β-oxidation (FAO) is essential for energy production and cellular homeostasis, yet its role in sperm function has remained unclear. Through whole-exome sequencing (WES) of 800 patients with asthenozoospermia, we identified biallelic Testis-Expressed Protein 44 (<i>TEX44)</i> variants in six individuals, all of whom exhibited defective mitochondrial sheath assembly and impaired sperm motility. Using <i>Tex44</i> knockout mice, we show that TEX44 interacts with carnitine palmitoyltransferase 1B (CPT1B) to form a mitochondrial glue, anchoring adjacent mitochondria and facilitating the assembly of the sperm-specific mitochondrial sheath. In vitro, we show that purified TEX44 protein can modulate CPT1B enzymatic activity, limiting the conversion of long-chain fatty acids such as palmitic acid and myristic acid into acyl-carnitines, thereby reducing reactive oxygen species (ROS) production. Loss of TEX44 disrupts this regulatory mechanism, leading to unregulated FAO, excessive ROS generation, and severe oxidative damage to sperm DNA and flagellar structure. Additionally, germ cell-specific <i>Cpt1b</i> knockout mice exhibit phenotypes similar to TEX44 deficiency, including mitochondrial sheath defects and reduced sperm motility. These findings reveal a sperm-specific mechanism by which TEX44 regulates CPT1B activity to balance FAO and ROS generation, providing critical insights into energy metabolism, mitochondrial integrity, and male infertility.</p>

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The TEX44-CPT1B axis regulates mitochondrial sheath assembly and fatty acid oxidation in sperm

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月23日

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  • Erlei Zhi,
  • Haowei Bai,
  • Chuan Ren,
  • Yue Dong,
  • Jintao Zhang,
  • Yanzhi Xu,
  • Chen Tan,
  • Yun Pan,
  • Lunni Zhou,
  • Peng Li,
  • Yueqiu Tan,
  • Yihong Zhou,
  • Lanlan Meng,
  • Junwei Xu,
  • Yuxiang Zhang,
  • Shuai Xu,
  • Zhiyong Ji,
  • Liangyu Zhao,
  • Min Jiang,
  • Zheng Li,
  • Chencheng Yao,
  • Yuchuan Zhou,
  • Jianping Wu,
  • Xiaoyu Yang,
  • Siyu Liu,
  • Mingxi Liu

摘要

Mitochondrial fatty acid β-oxidation (FAO) is essential for energy production and cellular homeostasis, yet its role in sperm function has remained unclear. Through whole-exome sequencing (WES) of 800 patients with asthenozoospermia, we identified biallelic Testis-Expressed Protein 44 (TEX44) variants in six individuals, all of whom exhibited defective mitochondrial sheath assembly and impaired sperm motility. Using Tex44 knockout mice, we show that TEX44 interacts with carnitine palmitoyltransferase 1B (CPT1B) to form a mitochondrial glue, anchoring adjacent mitochondria and facilitating the assembly of the sperm-specific mitochondrial sheath. In vitro, we show that purified TEX44 protein can modulate CPT1B enzymatic activity, limiting the conversion of long-chain fatty acids such as palmitic acid and myristic acid into acyl-carnitines, thereby reducing reactive oxygen species (ROS) production. Loss of TEX44 disrupts this regulatory mechanism, leading to unregulated FAO, excessive ROS generation, and severe oxidative damage to sperm DNA and flagellar structure. Additionally, germ cell-specific Cpt1b knockout mice exhibit phenotypes similar to TEX44 deficiency, including mitochondrial sheath defects and reduced sperm motility. These findings reveal a sperm-specific mechanism by which TEX44 regulates CPT1B activity to balance FAO and ROS generation, providing critical insights into energy metabolism, mitochondrial integrity, and male infertility.