Pradhan Bhola Shankar, Das Deepyaman, Sarkar Hironmoy, Bhattacharya Indrashis, Wadhwa Neerja, Majumdar Subeer S
Cellular Endocrinology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi 110067, India.
Łukasiewicz Research Network, PORT Polish Center for Technology Development, 147 Stabłowicka Street, 54-066 Wrocław, Poland.
Int J Mol Sci. 2025 Sep 20;26(18):9209. doi: 10.3390/ijms26189209.
Male infertility is a global health concern, and many cases are idiopathic in nature. The development and differentiation of germ cells (Gcs) are supported by Sertoli cells (Scs). Differentiated Scs support the development of Gcs into sperm, and hence, male fertility. We previously reported on a developmental switch in Scs around 12 days of age onwards in rats. During the process of the differentiation of Scs, the differential expression of mitophagy-related genes and its role in male fertility are poorly understood. To address this gap, we evaluated the microarray dataset GSE48795 to identify 12 mitophagy-related hub genes, including B-Cell Leukemia/Lymphoma 2 () and FBJ murine osteosarcoma viral oncogene homolog (). We identify Neuron-derived orphan receptor 1 () as a potential mitophagy-related gene of interest due to its strong regulatory association with two hub genes, and , which were differentially expressed during Sc maturation. To validate this finding, we generated a transgenic rat model with the Sc-specific knockdown of during puberty. A functional analysis showed impaired spermatogenesis with reduced fertility in these transgenic rats. Our findings suggest that may be an important mitophagy-related gene regulating the function of Scs and thereby regulating male fertility.
男性不育是一个全球性的健康问题，许多病例本质上是特发性的。生殖细胞（Gcs）的发育和分化由支持细胞（Scs）支持。分化后的支持细胞支持生殖细胞发育成精子，从而维持男性生育能力。我们之前报道过，在大鼠出生后约12天起，支持细胞会发生发育转变。在支持细胞分化过程中，线粒体自噬相关基因的差异表达及其在男性生育中的作用尚不清楚。为了填补这一空白，我们评估了基因芯片数据集GSE48795，以鉴定12个线粒体自噬相关的关键基因，包括B细胞淋巴瘤2（）和FBJ小鼠骨肉瘤病毒癌基因同源物（）。我们将神经源孤儿受体1（）确定为一个潜在的线粒体自噬相关的感兴趣基因，因为它与两个关键基因和有很强的调控关联，这两个基因在支持细胞成熟过程中差异表达。为了验证这一发现，我们构建了一个在青春期特异性敲低支持细胞中该基因的转基因大鼠模型。功能分析表明，这些转基因大鼠的精子发生受损，生育能力下降。我们的研究结果表明，该基因可能是一个重要的线粒体自噬相关基因，调节支持细胞的功能，从而调节男性生育能力。
