1. Academic Validation
  2. ClpP/ClpX deficiency impairs mitochondrial functions and mTORC1 signaling during spermatogenesis

ClpP/ClpX deficiency impairs mitochondrial functions and mTORC1 signaling during spermatogenesis

  • Commun Biol. 2023 Oct 5;6(1):1012. doi: 10.1038/s42003-023-05372-2.
Chenxi Guo 1 2 Yuan Xiao 3 Jingkai Gu 3 Peikun Zhao 3 Zhe Hu 4 Jiahuan Zheng 4 Renwu Hua 3 5 Zhuo Hai 3 Jiaping Su 3 Jian V Zhang 5 6 William S B Yeung 3 4 Tianren Wang 7
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China. chancy9199@sina.com.
  • 2 Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. chancy9199@sina.com.
  • 3 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
  • 4 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 999077, China.
  • 5 Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 6 Shenzhen Key Laboratory of Metabolic Health, Shenzhen, 518055, China.
  • 7 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China. wtrcmu@126.com.
Abstract

Caseinolytic Protease proteolytic subunit (ClpP) and caseinolytic Protease X (ClpX) are mitochondrial matrix peptidases that activate mitochondrial unfolded protein response to maintain protein homeostasis in the mitochondria. However, the role of ClpP and ClpX in spermatogenesis remains largely unknown. In this study, we demonstrated the importance of ClpP/ClpX for meiosis and spermatogenesis with two conditional knockout (cKO) mouse models. We found that ClpP/ClpX deficiency reduced mitochondrial functions and quantity in spermatocytes, affected energy supply during meiosis and attenuated zygotene-pachytene transformation of the male germ cells. The dysregulated spermatocytes finally underwent Apoptosis resulting in decreased testicular size and vacuolar structures within the seminiferous tubules. We found mTORC1 pathway was over-activated after deletion of ClpP/ClpX in spermatocytes. Long-term inhibition of the mTORC1 signaling via rapamycin treatment in vivo partially rescue spermatogenesis. The data reveal the critical roles of ClpP and ClpX in regulating meiosis and spermatogenesis.

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