Grim-19 plays a key role in mitochondrial steroidogenic acute regulatory protein stability and ligand-binding properties in Leydig cells.
Grim-19 plays a key role in mitochondrial steroidogenic acute regulatory protein stability and ligand-binding properties in Leydig cells.
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DOI：
10.1016/j.jbc.2022.102671
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发表时间：
2022-12
影响因子：
4.8
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Qu, Hu;He, Ke;Zou, Zi-hao;Niu, Gang;Lu, Li;Yao, Bing;Zhong, Wen-wen;Wang, De-juan;Li, Wei
Grim-19（gene associated with retinoid-IFN-induced mortality 19）是线粒体呼吸链复合体I的重要组成部分，通过控制细胞凋亡和能量代谢发挥非典型肿瘤抑制因子的作用。然而，最近有人提出Grim-19在男性生殖中的其他生物学作用。我们研究了Grim-19在小鼠睾丸中的表达和功能作用。从小鼠青春期检测到睾丸Grim-19表达，此后逐渐增加，并且观察到GRIM-19蛋白仅在间质Leydig细胞（LC）中表达，具有突出的线粒体定位。在体内慢病毒载体介导的Grim-19的敲低导致睾酮产生的显着减少，并引发睾丸中的异常氧化应激，从而通过诱导生殖细胞凋亡和少精子症损害男性生育力。使用分离的原代LC的体内敲低模型和MA-10小鼠Leydig肿瘤细胞的体外实验验证了GRIM-19对睾丸类固醇生成的控制。从机制上讲，我们认为GRIM-19缺陷诱导的氧化应激对类固醇生成的负调节可能是两种现象的结果：通过抑制类固醇生成急性调节蛋白（星星）磷酸化产生直接作用以及随后阻碍星星在线粒体中的定位和促进细胞外基质对类固醇生成能力的抑制作用的间接途径。LC通过促进整合素活化。总之，我们的观察表明，Grim-19在睾丸类固醇生成中起着重要作用，其改变可能导致与代谢应激和男性不育相关的睾酮缺乏相关疾病。
Grim-19 (gene associated with retinoid-IFN–induced mortality 19), the essential component of complex I of mitochondrial respiratory chain, functions as a noncanonical tumor suppressor by controlling apoptosis and energy metabolism. However, additional biological actions of Grim-19 have been recently suggested in male reproduction. We investigated here the expression and functional role of Grim-19 in murine testis. Testicular Grim-19 expression was detected from mouse puberty and increased progressively thereafter, and GRIM-19 protein was observed to be expressed exclusively in interstitial Leydig cells (LCs), with a prominent mitochondrial localization. In vivo lentiviral vector–mediated knockdown of Grim-19 resulted in a significant decrease in testosterone production and triggered aberrant oxidative stress in testis, thus impairing male fertility by inducing germ cell apoptosis and oligozoospermia. The control of testicular steroidogenesis by GRIM-19 was validated using the in vivo knockdown model with isolated primary LCs and in vitro experiments with MA-10 mouse Leydig tumor cells. Mechanistically, we suggest that the negative regulation exerted by GRIM-19 deficiency-induced oxidative stress on steroidogenesis may be the result of two phenomena: a direct effect through inhibition of phosphorylation of steroidogenic acute regulatory protein (StAR) and subsequent impediment to StAR localization in mitochondria and an indirect pathway that is to facilitate the inhibiting role exerted by the extracellular matrix on the steroidogenic capacity of LCs via promotion of integrin activation. Altogether, our observations suggest that Grim-19 plays a potent role in testicular steroidogenesis and that its alterations may contribute to testosterone deficiency-related disorders linked to metabolic stress and male infertility.
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