Caliban regulates mitochondrial morphology and redox state in enterocytes to maintain intestinal homeostasis in Drosophila
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PROVIDER: PRJNA515000 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description: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.
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