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Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

Author

Listed:
  • Senyu Yao

    (The Seventh Affiliated Hospital of Sun Yat-sen University
    Sun Yat-Sen University)

  • Xiaoyue Wei

    (The Seventh Affiliated Hospital of Sun Yat-sen University
    Sun Yat-Sen University)

  • Wenrui Deng

    (The Seventh Affiliated Hospital of Sun Yat-sen University
    Sun Yat-Sen University)

  • Boyan Wang

    (The Seventh Affiliated Hospital of Sun Yat-sen University
    Sun Yat-Sen University)

  • Jianye Cai

    (Sun Yat-Sen University
    Sun Yat-Sen University)

  • Yinong Huang

    (Sun Yat-Sen University
    The First Affiliated Hospital of Sun Yat-Sen University)

  • Xiaofan Lai

    (Sun Yat-Sen University
    Sun Yat-sen University)

  • Yuan Qiu

    (Sun Yat-Sen University)

  • Yi Wang

    (Sun Yat-Sen University)

  • Yuanjun Guan

    (Sun Yat-Sen University)

  • Jiancheng Wang

    (The Seventh Affiliated Hospital of Sun Yat-sen University
    Sun Yat-Sen University
    Sun Yat-Sen University)

Abstract

Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases.

Suggested Citation

  • Senyu Yao & Xiaoyue Wei & Wenrui Deng & Boyan Wang & Jianye Cai & Yinong Huang & Xiaofan Lai & Yuan Qiu & Yi Wang & Yuanjun Guan & Jiancheng Wang, 2022. "Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31755-w
    DOI: 10.1038/s41467-022-31755-w
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    References listed on IDEAS

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    1. Jiancheng Wang & Qiying Lu & Jianye Cai & Yi Wang & Xiaofan Lai & Yuan Qiu & Yinong Huang & Qiong Ke & Yanan Zhang & Yuanjun Guan & Haoxiang Wu & Yuanyuan Wang & Xin Liu & Yue Shi & Kang Zhang & Maosh, 2019. "Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
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    1. Ani Chi & Bicheng Yang & Hao Dai & Xinyu Li & Jiahui Mo & Yong Gao & Zhihong Chen & Xin Feng & Menghui Ma & Yanqing Li & Chao Yang & Jie Liu & Hanchao Liu & Zhenqing Wang & Feng Gao & Yan Liao & Xueta, 2024. "Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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