In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.

中文翻译：

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MITOL 功能障碍导致侏儒症伴垂体前叶发育不全。

在线粒体疾病中，身材矮小和生长障碍是常见症状，但其潜在机制尚不清楚。在这项研究中，我们研究了由巢蛋白启动子驱动的线粒体泛素连接酶 MITOL (MARCH5) 敲除诱导的小鼠生长失败的原因，线粒体泛素连接酶 MITOL (MARCH5) 是线粒体功能的关键调节因子。MITOL 基因敲除小鼠因垂体转录因子 1 (Pit1) 表达降低而出现先天性垂体前叶发育不全。一致地，在突变小鼠的垂体前叶中，生长激素 (GH) 的 mRNA 水平和催乳素水平均显着降低。通过皮下注射重组GH，部分地挽救了突变小鼠的生长失败。为了阐明这种异常是由垂体前叶中 MITOL 敲低的主要作用还是其他病变的次要作用引起的，我们对培养的大鼠垂体 GH3 细胞（分泌 GH）进行了慢病毒介导的 MITOL 敲低。在 MITOL 敲低的 GH3 细胞中，GH 的产生严重受损。总之，MITOL 在垂体前叶的发育中起着关键作用；因此，MITOL 功能障碍小鼠表现出垂体前叶发育不全引起的垂体侏儒症。我们的研究结果表明，线粒体功能障碍通常与垂体性侏儒症的未知发病机制有关。MITOL 在垂体前叶的发育中起着关键作用；因此，MITOL 功能障碍小鼠表现出垂体前叶发育不全引起的垂体侏儒症。我们的研究结果表明，线粒体功能障碍通常与垂体性侏儒症的未知发病机制有关。MITOL 在垂体前叶的发育中起着关键作用；因此，MITOL 功能障碍小鼠表现出垂体前叶发育不全引起的垂体侏儒症。我们的研究结果表明，线粒体功能障碍通常与垂体性侏儒症的未知发病机制有关。