Li Leilei, Xiao Yanhui, Liu Liansheng, Zhang Qianying, Zhang Yong, Zhu Dahai, Chen Ye-Guang
Guangzhou National Laboratory, Guangzhou, China.
Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, China.
Cell Regen. 2025 Jun 9;14(1):23. doi: 10.1186/s13619-025-00243-z.
Intestinal homeostasis is sustained by self-renewal of intestinal stem cells (ISCs), which continuously divide and produce proliferative transit-amplifying (TA) and then progenitor cells. Eukaryotic translation initiation factor 5A (eIF5A), a conserved translation factor, involves in a variety of cellular processes, yet its role in intestinal homeostasis remains unclear. Here, we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis. Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss, suppressed cell proliferation, and increased apoptosis within the crypts, concurrent with shortened gut length, reduced mouse body weight and rapid animal mortality. Consistently, Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes. Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins, particularly those involved in mitochondrial translation, upon eIF5A depletion. Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes, including Dars2, are highly expressed in ISC, TA and progenitor cells. Furthermore, eIF5A-deficient organoids exhibit impaired mitochondrial function, characterized by reduced ATP levels and increased reactive oxygen species (ROS). These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation, providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.
肠道稳态由肠道干细胞（ISC）的自我更新维持，肠道干细胞不断分裂并产生增殖性的过渡放大（TA）细胞，然后产生祖细胞。真核生物翻译起始因子5A（eIF5A）是一种保守的翻译因子，参与多种细胞过程，但其在肠道稳态中的作用仍不清楚。在这里，我们证明eIF5A对于维持肠道上皮稳态是不可或缺的。在成年小鼠肠道上皮中条件性敲除Eif5a会导致干细胞丢失、细胞增殖受抑制以及隐窝内细胞凋亡增加，同时伴有肠道长度缩短、小鼠体重减轻和动物快速死亡。同样，在肠道类器官中敲除Eif5a也表现出类似的细胞表型。质谱分析显示，eIF5A缺失后线粒体蛋白显著下调，尤其是那些参与线粒体翻译的蛋白。对已发表的单细胞RNA测序数据集的分析表明，包括Dars2在内的线粒体翻译相关基因在ISC、TA和祖细胞中高度表达。此外，缺乏eIF5A的类器官表现出线粒体功能受损，其特征是ATP水平降低和活性氧（ROS）增加。这些发现突出了eIF5A在通过调节线粒体翻译维持肠道上皮稳态中的关键作用，为肠道干细胞更新和组织维持的分子机制提供了新的见解。
