Polyamines regulate mitochondrial metabolism essential for intestinal epithelial renewal and wound healing

Homeostasis of the mammalian intestinal epithelium is tightly regulated by multiple factors, including cellular polyamines, but the exact mechanism underlying polyamines in this process remains largely unknown. Mitochondria are the powerhouse of cells and can also function as signaling organelles by releasing metabolic by-products. Here, we determined whether polyamines regulate intestinal epithelial renewal and wound healing by altering mitochondrial activity. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with α-difluoromethylornithine (DFMO) resulted in mitochondrial dysfunction as evidenced by decreases in basal and maximal respiration levels, ATP production, and spare respiration capacity. Polyamine depletion by DFMO also decreased the levels of mitochondria-associated proteins prohibitin 1 and COX-IV. Mitochondrial dysfunction induced by DFMO was associated with an inhibition of intestinal organoid growth and epithelial repair after wounding, and this inhibition was ameliorated by administration of the mitochondrial activator Mito-Tempo or exogenous polyamine putrescine. These results indicate that polyamines are necessary for mitochondrial metabolism, in turn, controlling constant intestinal mucosal growth and epithelial repair after acute injury. NEW & NOTEWORTHY Our results indicate that polyamines are required for maintaining mitochondrial integrity in intestinal epithelial cells. Polyamine depletion led to mitochondrial dysfunction, along with an inhibition of intestinal epithelial renewal and delayed wound healing. Reinforcing mitochondrial activity by Mito-Tempo ameliorated reduced epithelial renewal and delayed healing in polyamine-deficient cells, demonstrating the importance of mitochondrial metabolism in polyamine-regulated mucosal growth and repair after injury.