The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
School of Medicine, Nantong University, Nantong, China.
PLoS Genet. 2020 Oct 15;16(10):e1009140. doi: 10.1371/journal.pgen.1009140. eCollection 2020 Oct.
Precise regulation of stem cell activity is crucial for tissue homeostasis. In Drosophila, intestinal stem cells (ISCs) maintain the midgut epithelium and respond to oxidative challenges. However, the connection between intestinal homeostasis and redox signaling remains obscure. Here we find that Caliban (Clbn) functions as a regulator of mitochondrial dynamics in enterocytes (ECs) and is required for intestinal homeostasis. The clbn knock-out flies have a shortened lifespan and lose the intestinal homeostasis. Clbn is highly expressed and localizes to the outer membrane of mitochondria in ECs. Mechanically, Clbn mediates mitochondrial dynamics in ECs and removal of clbn leads to mitochondrial fragmentation, accumulation of reactive oxygen species, ECs damage, activation of JNK and JAK-STAT signaling pathways. Moreover, multiple mitochondria-related genes are differentially expressed between wild-type and clbn mutated flies by a whole-genome transcriptional profiling. Furthermore, loss of clbn promotes tumor growth in gut generated by activated Ras in intestinal progenitor cells. Our findings reveal an EC-specific function of Clbn in regulating mitochondrial dynamics, and provide new insight into the functional link among mitochondrial redox modulation, tissue homeostasis and longevity.
精确调节干细胞活性对于组织稳态至关重要。在果蝇中，肠道干细胞（ISCs）维持中肠上皮，并对氧化应激做出响应。然而，肠道稳态和氧化还原信号之间的联系仍不清楚。在这里，我们发现 Caliban（Clbn）作为肠细胞（ECs）中线粒体动力学的调节剂发挥作用，并且是肠道稳态所必需的。clbn 敲除果蝇的寿命缩短，并且失去了肠道稳态。Clbn 在 ECs 中高表达并定位于线粒体的外膜。在机制上，Clbn 介导 ECs 中线粒体动力学，去除 clbn 导致线粒体碎片化、活性氧积累、ECs 损伤、JNK 和 JAK-STAT 信号通路激活。此外，通过全基因组转录谱分析，在野生型和 clbn 突变果蝇之间，多个与线粒体相关的基因表达存在差异。此外，clbn 的缺失促进了由肠道祖细胞中激活的 Ras 产生的肠道中肿瘤的生长。我们的研究结果揭示了 Clbn 在调节线粒体动力学方面的 EC 特异性功能，并为线粒体氧化还原调节、组织稳态和寿命之间的功能联系提供了新的见解。
