Mathuram Theodore L, Su Yafei, Bard Jonathan E, Perry Noa A, Chen Chien Wen, Warren Marisa T, Linden Phillip A, Perry Yaron, Hatzoglou Maria, Wu Yun, Blumental-Perry Anna
bioRxiv. 2024 Jan 15:2024.01.14.575591. doi: 10.1101/2024.01.14.575591.
We showed that levels of a murine mitochondrial noncoding RNA, , increase in alveolar epithelial type 2 cells exposed to extracts from cigarette smoke. The transcripts translocate to the nucleus, upregulating nucleus-encoded mitochondrial genes and mitochondrial bioenergetics. This response is lost after chronic exposure to smoke in a mouse model of chronic obstructive pulmonary disease.
To determine if plays a role in human disease, this study aimed to (i) identify the human homologue, (ii) test if the smoke-induced response occurs in human cells, (ii) determine causality between the subcellular localization of the transcript and increased mitochondrial bioenergetics, and (iii) analyze transcript levels in samples from patients with chronic obstructive pulmonary disease.
Levels and subcellular localization of the human homologue identified from an RNA transcript library were assessed in human alveolar epithelial type 2 cells exposed to smoke extract. Lipid nanoparticles were used for nucleus-targeted delivery of transcripts. Analyses included hybridization, quantitative PCR, cell growth, and Seahorse mitochondrial bioenergetics assays.
The levels of human homologue transiently increased and the transcripts translocated to the nuclei in human cells exposed to smoke extract. Targeted nuclear delivery of transcripts increased mitochondrial bioenergetics. Alveolar cells from humans with chronic obstructive pulmonary disease had reduced levels of the .
mediates mitochondrial bioenergetics in murine and human alveolar epithelial type 2 cells in response to cigarette smoke exposure, but this response is likely lost in diseases associated with chronic smoking, such as chronic obstructive pulmonary disease, due to its diminished levels.
This study describes a novel mechanism by which epithelial cells in the lungs adapt to the mitochondrial stress triggered by exposure to cigarette smoke. We show that a noncoding RNA in mitochondria is upregulated and translocated to the nuclei of alveolar epithelial type 2 cells to trigger expression of genes that restore mitochondrial bioenergetics. Mitochondria function and levels of the noncoding RNA decrease under conditions that lead to chronic obstructive pulmonary disease, suggesting that the mitochondrial noncoding RNA can serve as potential therapeutic target to restore function to halt disease progression.
我们发现，一种小鼠线粒体非编码RNA，在暴露于香烟烟雾提取物的肺泡Ⅱ型上皮细胞中的水平会升高。这些转录本会转移至细胞核，上调核编码的线粒体基因以及线粒体生物能量学相关基因。在慢性阻塞性肺疾病小鼠模型中，长期暴露于烟雾后这种反应会消失。
为了确定是否在人类疾病中起作用，本研究旨在：（i）鉴定人类同源物；（ii）检测烟雾诱导的反应是否在人类细胞中发生；（ii）确定转录本的亚细胞定位与线粒体生物能量学增加之间的因果关系；（iii）分析慢性阻塞性肺疾病患者样本中的转录水平。
在暴露于烟雾提取物的人类肺泡Ⅱ型上皮细胞中，评估从RNA转录文库中鉴定出的人类同源物的水平和亚细胞定位。脂质纳米颗粒用于将转录本靶向递送至细胞核。分析包括杂交、定量PCR、细胞生长和海马体线粒体生物能量学检测。
在暴露于烟雾提取物的人类细胞中，人类同源物的水平短暂升高，转录本转移至细胞核。转录本的靶向核递送增加了线粒体生物能量学。慢性阻塞性肺疾病患者的肺泡细胞中的水平降低。
在小鼠和人类肺泡Ⅱ型上皮细胞中，介导对香烟烟雾暴露的线粒体生物能量学反应，但由于其水平降低，在与长期吸烟相关的疾病（如慢性阻塞性肺疾病）中，这种反应可能会消失。
本研究描述了一种新机制，肺部上皮细胞通过该机制适应由接触香烟烟雾引发的线粒体应激。我们表明，线粒体中的一种非编码RNA被上调并转移至肺泡Ⅱ型上皮细胞的细胞核，以触发恢复线粒体生物能量学的基因表达。在导致慢性阻塞性肺疾病的条件下，线粒体功能和非编码RNA水平降低，这表明线粒体非编码RNA可作为恢复功能以阻止疾病进展的潜在治疗靶点。
