Caliban regulates mitochondrial morphology and redox state in enterocytes to maintain intestinal homeostasis in Drosophila

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 by increasing proliferation rates. However, the connection between intestinal homeostasis and redox signaling remains obscure. Here we identify Caliban (Clbn) as a novel mitochondrial protein involved in regulating the cellular redox state in enterocytes (ECs) and the proliferative activity of ISCs. We find that clbn knock-out flies lose the intestinal homeostasis characterized by increased ISCs proliferation, disrupted intestinal epithelial integrity, reduced viability in response to harmful stress and shortened lifespan. Mechanistically, Clbn is highly expressed and localized to mitochondria in ECs, and loss of clbn impairs mitochondrial morphology and functions, result in accumulation of reactive oxygen species, ECs damage and activation of JNK and JAK-STAT signaling pathways. Furthermore, loss of clbn promotes tumor growth in gut generated by activating Ras in intestinal progenitor cells. Our findings reveal the essential role of Clbn in maintaining intestinal homeostasis and may provide new insight into the functional link among mitochondrial redox modulation, tissue homeostasis and cancer. Gene expression was profiled in 6 samples [embryos of w1118 and clbn knock-out flies, 3 replicates].