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.

中文翻译：

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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底祖细胞功能


基底细胞 （BCs） 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 （MPC） 充当对 BC 命运决定至关重要的代谢检查点。抑制 MPC 使小鼠和人类的 BC 能够长期扩增。小鼠中 Mpc2 的基因失活导致体内平衡期间 BC 增生和纤毛细胞减少，以及损伤后上皮再生和中间细胞积累延迟。从机制上讲，MPC2 将糖酵解与 ATP 柠檬酸裂解酶 （ACLY） 依赖性胞质乙酰辅酶 A （CoA） 生成联系起来，这是分化相关基因转录的表观遗传控制所必需的。调节这种代谢表观遗传轴部分挽救了 Yes 相关蛋白 （YAP） 功能障碍诱导的 BC 变化。重要的是，外源性柠檬酸盐促进了 BCs 与慢性阻塞性肺病 （COPD） 患者的分化。因此，除了证明丙酮酸代谢在 BC 命运决定中的作用外，我们的研究表明，靶向丙酮酸-柠檬酸盐代谢可能作为纠正肺部疾病中异常 BC 行为的潜在策略。