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Researchers studying fruit fly intestinal cells have discovered that the small molecule heme acts as a regulatory brake on erebosis, a recently identified form of cell death distinct from apoptosis, autophagy, or necrosis. Through single-cell RNA sequencing and genetic experiments, they found that cells preparing to undergo erebosis actively reduce their heme levels by increasing heme-degrading enzymes and exporters, and that artificially maintaining high heme levels prevents this death process. The study reveals that heme depletion initiates erebosis through Dpp signaling, which in turn coordinates with intestinal stem cell proliferation to maintain gut tissue balance.
Why it matters
This discovery establishes the first molecular mechanism controlling erebosis and demonstrates how metabolite regulation can coordinate cell death with stem cell division to maintain tissue health. Understanding this process could have implications for intestinal diseases and aging-related tissue dysfunction, as similar mechanisms may exist in mammalian gut homeostasis.
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by Motohiro Morikawa, Tetsutaro Hayashi, Yuko Ikegawa, Tomomi Takano, Kazuya Wata, Hirohisa Kyogoku, Mariko Kuse, Mika Yoshimura, Hiroshi Nishida, Rahul Parit, Dao My Linh, Kanta Kawai, Tasuku Hirayama, Chun Wang Sy, Kan Etoh, Itoshi Nikaido, Sa Kan Yoo
Tissue homeostasis relies on the balance between proliferation of stem cells and death of differentiated cells. In Drosophila gut enterocytes, we recently identified a novel form of cell death, termed erebosis. Erebosis is a nonapoptotic, nonautophagic, and nonnecrotic process, in which affected cells accumulate Ance (angiotensin-converting enzyme) and lose many other proteins, ultimately leading to the loss of organelles and the nucleus. The underlying molecular mechanism of erebosis has remained unclear. Here, through single-cell RNA sequencing and genetic approaches, we found that the small metabolite heme regulates erebosis. Cells undergoing erebosis up-regulate the heme-degrading enzyme Heme oxygenase (Ho) and the heme exporter Mrp5, and decrease intracellular amounts of heme. Heme depletion by Mrp5 overexpression promotes erebosis, whereas heme accumulation by knockdown of Ho or Mrp5, or by feeding a heme precursor, suppresses it. Downstream of heme, Dpp signaling suppresses erebosis. Inhibition of erebosis reduces intestinal stem cell proliferation, indicating a cross-talk mechanism between enterocyte death and stem cell division. Our results demonstrate that reduction of cytoplasmic heme is a critical step in initiating enterocyte erebosis and coordinating stem cell proliferation, thereby maintaining gut tissue homeostasis. This work provides the first insight into the molecular mechanism regulating erebosis.
Source: Heme acts as a metabolic brake on erebosis in the <i>Drosophila</i> gut