Abstract：
The mitochondrial translocator protein (18 kDa; TSPO) is a high-affinity cholesterol-binding protein that is an integral component of the cholesterol trafficking scaffold responsible for determining the rate of cholesterol import into the mitochondria for steroid biosynthesis. Previous studies have shown that TSPO declines in aging Leydig cells (LCs) and that its decline is associated with depressed circulating testosterone levels in aging rats. However, TSPO\'s role in the mechanistic decline in LC function is not fully understood. To address the role of TSPO depletion in LC function, we first examined mitochondrial quality in Tspo knockout mouse tumor MA-10 nG1 LCs compared to wild-type MA-10 cells. Tspo deletion caused a disruption in mitochondrial function and membrane dynamics. Increasing mitochondrial fusion via treatment with the mitochondrial fusion promoter M1 or by optic atrophy 1 (OPA1) overexpression resulted in the restoration of mitochondrial function and mitochondrial morphology as well as in steroid formation in TSPO-depleted nG1 LCs. LCs isolated from aged rats form less testosterone than LCs isolated from young rats. Treatment of aging LCs with M1 improved mitochondrial function and increased androgen formation, suggesting that aging LC dysfunction may stem from compromised mitochondrial dynamics caused by the age-dependent LC TSPO decline. These results, taken together, suggest that maintaining or enhancing mitochondrial fusion may provide therapeutic strategies to maintain or restore testosterone levels with aging.
摘要：
线粒体转运蛋白（18kDa；TSPO）是一种高亲和力的胆固醇结合蛋白，是胆固醇运输支架的组成部分，负责确定胆固醇进入线粒体进行类固醇生物合成的速率。先前的研究表明，TSPO在衰老的Leydig细胞（LCs）中下降，并且其下降与衰老大鼠的循环睾丸激素水平下降有关。然而,TSPO在LC功能机制下降中的作用尚不完全清楚。为了解决TSPO耗尽在LC功能中的作用，我们首先检查了Tspo敲除小鼠肿瘤MA-10nG1LC与野生型MA-10细胞的线粒体质量。Tspo缺失导致线粒体功能和膜动力学的破坏。通过用线粒体融合启动子M1处理或通过视神经萎缩1（OPA1）过表达增加线粒体融合，导致线粒体功能和线粒体形态的恢复以及TSPO耗尽的nG1LC中的类固醇形成。从老年大鼠中分离的LC比从年轻大鼠中分离的LC形成更少的睾酮。用M1治疗衰老LCs可改善线粒体功能并增加雄激素形成，提示衰老LC功能障碍可能源于年龄依赖性LCTSPO下降引起的线粒体动力学受损。这些结果,放在一起，提示维持或增强线粒体融合可能提供治疗策略,以维持或恢复睾酮水平随着年龄的增长.
