Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.

中文翻译：

---

线粒体长链非编码 RNA lncMtloop 调节线粒体转录并抑制阿尔茨海默病。


维持线粒体稳态对于细胞存活和机体健康至关重要，线粒体功能障碍与包括阿尔茨海默病 （AD） 在内的各种疾病之间的联系证明了这一点。在这里，我们报道了 lncMtDloop 是一种在线粒体基因组 D 环区域编码的未知功能的非编码 RNA，它随着年龄的增长而维持线粒体 RNA 水平和功能。lncMtDloop 在人类 AD 患者和 3xTg AD 小鼠模型的大脑中表达降低。此外，lncMtDloop 与线粒体转录因子 A （TFAM） 结合，促进 TFAM 募集到 mtDNA 启动子，并增加线粒体转录。为了允许 lncMtDloop 通过 PNPASE 依赖性运输途径转运到线粒体中，我们将线粒体核糖体蛋白 S12 （MRPS12） 的 3'UTR 定位序列融合到其末端，产生指定的茎环结构。将这种同素异形体 lncMtDloop 引入 AD 模型小鼠中可显著改善线粒体功能和形态，并改善 AD 模型小鼠的 AD 样病理和行为缺陷。综上所述，这些数据为 lncMtDloop 作为线粒体转录调节因子及其对阿尔茨海默病发病机制的贡献提供了见解。