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

Senyu Yao, Xiaoyue Wei, Wenrui Deng, Boyan Wang, Jianye Cai, Yinong Huang, Xiaofan Lai, Yuan Qiu, Yi Wang, Yuanjun Guan and Jiancheng Wang ()
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Senyu Yao: The Seventh Affiliated Hospital of Sun Yat-sen University
Xiaoyue Wei: The Seventh Affiliated Hospital of Sun Yat-sen University
Wenrui Deng: The Seventh Affiliated Hospital of Sun Yat-sen University
Boyan Wang: The Seventh Affiliated Hospital of Sun Yat-sen University
Jianye Cai: Sun Yat-Sen University
Yinong Huang: Sun Yat-Sen University
Xiaofan Lai: 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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31755-w

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