线粒体丙酮酸载体通过糖酵解-表观遗传重编程控制气道基础祖细胞功能

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui
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引用次数: 0

摘要

基底细胞(BC)是负责气管上皮完整性的祖细胞。在这里,我们证明了线粒体丙酮酸载体(MPCs)作为新陈代谢的检查点对BC命运的决定至关重要。抑制线粒体丙酮酸载体可使小鼠和人类的BC长期扩增。小鼠 Mpc2 基因失活会导致 BC 增生和纤毛细胞减少,以及上皮再生延迟和损伤后中间细胞堆积。从机理上讲,MPC2 将糖酵解与依赖于细胞膜乙酰辅酶 A(CoA)生成的柠檬酸ATP裂解酶(ACLY)联系起来,而乙酰辅酶 A 是分化相关基因转录的表观遗传控制所必需的。调节这一代谢-表观遗传轴可部分缓解Yes相关蛋白(YAP)功能障碍诱导的BC变化。重要的是,外源性柠檬酸盐能促进慢性阻塞性肺病(COPD)患者 BCs 的分化。因此,除了证明丙酮酸代谢在BC命运决定中的作用外,我们的研究还表明,靶向丙酮酸-柠檬酸代谢可能是纠正肺部疾病中异常BC行为的一种潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming

Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming
Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of Mpc2 in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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