PDF(Pubmed)
Abstract：
Background: The interstitial testicular Leydig cells are responsible for the production of testosterone, which functionally deteriorate with normal aging. Decreased expression of mitochondrial steroidogenic interactome proteins and diminished mitochondrial function in aging Leydig cells suggest that mitochondrial dynamics play a role in maintaining adequate levels of testosterone. Optic atrophy 1 (OPA1) protein regulates mitochondrial dynamics and cristae formation in many cell types. Previous studies showed that increasing OPA1 expression in dysfunctional Leydig cells restored mitochondrial function and recovered androgen production to levels found in healthy Leydig cells. These findings suggested that mitochondrial dynamics may be a promising target to ameliorate diminished testosterone levels in aging males. Methods: We used twelve-month-old rats to explore the relationship between mitochondrial dynamics and Leydig cell function. Isolated Leydig cells from aged rats were treated ex vivo with the cell-permeable mitochondrial fusion promoter 4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl)hydrazono)ethyl) phenol (mitochondrial fusion promoter M1), which enhances mitochondrial tubular network formation. In parallel, rats were treated with 2 mg/kg/day M1 for 6 weeks before Leydig cells were isolated. Results: Ex vivo M1-treated cells showed enhanced mitochondrial tubular network formation by transmission electron microscopy, enhanced Leydig cell mitochondrial integrity, improved mitochondrial function, and higher testosterone biosynthesis compared to controls. However, in vivo treatment of aged rats with M1 not only failed to re-establish testosterone levels to that of young rats, it also led to further reduction of testosterone levels and increased apoptosis, suggesting M1 toxicity in the testis. The in vivo M1 toxicity seemed to be tissue-specific, however. Conclusion: Promoting mitochondrial fusion may be one approach to enhancing cell health and wellbeing with aging, but more investigations are warranted. Our findings suggest that fusion promoters could potentially enhance the productivity of aged Leydig cells when carefully regulated.
摘要：
背景：间质睾丸间质细胞负责睾丸激素的产生，功能随着正常老化而恶化。在衰老的Leydig细胞中，线粒体类固醇生成相互作用蛋白的表达降低和线粒体功能减弱表明，线粒体动力学在维持适当的睾酮水平中起作用。视神经萎缩1（OPA1）蛋白调节许多细胞类型的线粒体动力学和cr形成。先前的研究表明，在功能失调的Leydig细胞中增加OPA1表达可以恢复线粒体功能，并将雄激素产生恢复到健康Leydig细胞中的水平。这些发现表明，线粒体动力学可能是改善衰老男性睾丸激素水平降低的有希望的目标。方法：我们使用12月龄大鼠，探讨线粒体动力学与睾丸间质细胞功能之间的关系。用细胞通透性线粒体融合启动子4-氯-2-（1-（2-（2,4,6-三氯苯基）肼基）乙基）苯酚（线粒体融合启动子M1）离体处理来自老年大鼠的Leydig细胞，从而增强线粒体肾小管网络的形成。并行,在分离Leydig细胞之前,用2mg/kg/天M1处理大鼠6周。结果：离体M1处理的细胞通过透射电子显微镜显示增强的线粒体肾小管网络形成，增强睾丸间质细胞线粒体完整性，改善线粒体功能，与对照组相比，睾酮的生物合成更高。然而,用M1对老年大鼠的体内治疗不仅无法重新建立年轻大鼠的睾丸激素水平，它还导致睾酮水平进一步降低和细胞凋亡增加，提示睾丸中的M1毒性。体内M1毒性似乎是组织特异性的，however.结论：促进线粒体融合可能是随着衰老增强细胞健康和福祉的一种方法。但需要更多的调查.我们的发现表明，当仔细调节时，融合启动子可能会提高老化的Leydig细胞的生产率。
