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

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 () and Mingxi Liu ()
Additional contact information
Erlei Zhi: Shanghai Jiao Tong University School of Medicine
Haowei Bai: Shanghai Jiao Tong University School of Medicine
Chuan Ren: Nanjing Medical University
Yue Dong: Nanjing Medical University
Jintao Zhang: The First Affiliated Hospital of Nanjing Medical University
Yanzhi Xu: Westlake University
Chen Tan: Central South University
Yun Pan: Nanjing Medical University
Lunni Zhou: Westlake University
Peng Li: Shanghai Jiao Tong University School of Medicine
Yueqiu Tan: Central South University
Yihong Zhou: The Fifth Affiliated Hospital of Sun Yat-sen University
Lanlan Meng: Central South University
Junwei Xu: Shanghai Jiao Tong University School of Medicine
Yuxiang Zhang: Shanghai Jiao Tong University School of Medicine
Shuai Xu: Shanghai Jiao Tong University School of Medicine
Zhiyong Ji: Xiamen University
Liangyu Zhao: Sun Yat-sen University
Min Jiang: Westlake University
Zheng Li: Shanghai Jiao Tong University School of Medicine
Chencheng Yao: Shanghai Jiao Tong University School of Medicine
Yuchuan Zhou: Shanghai Jiao Tong University
Jianping Wu: Westlake University
Xiaoyu Yang: The First Affiliated Hospital of Nanjing Medical University
Siyu Liu: Nanjing Medical University
Mingxi Liu: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63280-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63280-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63280-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().