The S-depalmitoylase ABHD10 is essential for sperm mitochondrial sheath formation and male fertility

Shumin Zhou, Hao Zhou, Haoran Xu, Mengneng Xiong, Shiming Gan, Dalin Liu, Yifan Zhao, Ziqi Yu, Chunhai Luo, Yujun Zhang, Beibei Zhang and Fei Sun ()
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Shumin Zhou: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Hao Zhou: Hangzhou Medical College, School of Basic Medical Sciences and Forensic Medicine
Haoran Xu: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Mengneng Xiong: Renmin Hospital of Wuhan University, Center for Reproductive Medicine
Shiming Gan: Zhejiang University, Center for Reproductive Medicine, the Fourth Affiliated Hospital, International Institutes of Medicine
Dalin Liu: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Yifan Zhao: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Ziqi Yu: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Chunhai Luo: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Yujun Zhang: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Beibei Zhang: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital
Fei Sun: Zhejiang University School of Medicine, Department of Urology and Andrology, Sir Run Run Shaw Hospital

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

Abstract: Abstract Palmitoylation is the only fully reversible post-translational lipid modification that impacts 10-20% of the human proteome, but its role during spermatogenesis remains enigmatic. In this study, through generating HA-tagged Abhd10 knock-in mice, Abhd10-null mice, and combining super-resolution fluorescence imaging and electron microscopy, we identify that the S-depalmitoylase ABHD10 (abhydrolase domain containing 10) is a mitochondrial matrix protein, specifically expressed in testis and is essential for male fertility. Abhd10 knockout mice manifest severe sperm motility defects accompanied by malformed mitochondrial sheaths of sperm. Mitochondrial proteomic analysis reveals that ABHD10 deficiency downregulates respiratory chain complex proteins and mitochondrial sheath formation factors SPATA19 and GK2. Using mass spectrometry-based mitochondrial acyl-biotin exchange assays, we systematically identify that loss of ABHD10 leads to the hyper-palmitoylation of multiple functionally critical proteins, including mitochondrial sheath formation factors (SPATA19 and GK2) and aerobic respiration regulators (PDHX, NDUFV1 and SDHB). Co-immunoprecipitation and proximity labeling assays reveal the physical interactions between ABHD10 and its substrates (SPATA19, GK2, PDHX). Collectively, ABHD10 may bind to and mediate the S-depalmitoylation of SPATA19, GK2, and PDHX, thereby regulating the formation of the sperm mitochondrial sheath and mitochondrial function. This work not only identifies S-depalmitoylase ABHD10 as a key determinant of male fertility but also advances our understanding of post-translational regulation during spermatogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-65300-2

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