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

• Published in: Nature communications Vol. 13; no. 1; p. 4020
• Main Authors: Yao, Senyu, Wei, Xiaoyue, Deng, Wenrui, Wang, Boyan, Cai, Jianye, Huang, Yinong, Lai, Xiaofan, Qiu, Yuan, Wang, Yi, Guan, Yuanjun, Wang, Jiancheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/100; 13/109; 13/31; 13/44; 13/89; 14/19; 14/28; 14/34; 14/35; 45/77; 631/136/2434/1822; 631/80/128/1580; 631/80/509; 631/80/642/333; 64/60; 692/699/2732/2730; Aging; Cell differentiation; Cytoskeleton; Differentiation (biology); Endoplasmic reticulum; Homeostasis; Humanities and Social Sciences; Leydig cells; Lipid metabolism; Lipids; Male reproductive system; Males; Mitochondria; multidisciplinary; Nestin; Organelles; Regulatory mechanisms (biology); Reproductive system; Science; Science (multidisciplinary); Senescence; Stems; Substrates; Testosterone
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31755-w

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. The regulatory mechanisms contributing to male reproductive ageing are unknown. Here, the authors show that Nestin-dependent mito-ER contacts (MERCs) regulate stem Leydig cell (SLC) senescence and provide insights into SLCs-targeting therapies.