Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

dObjective Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn's disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD. Design Male and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1(i Delta IEC)) or Paneth cell-specific deletion of Phb1 (Phb1(Delta PC)) and Phb1(fl/fl) control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1(i Delta IEC) or Phb1(Delta PC) mice. Results Phb1(i Delta IEC) mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1(i Delta IEC) ileum. Deletion of Phb1 specifically in Paneth cells (Phb1(Delta PC)) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1(i Delta IEC) or Phb1(Delta PC) mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo. Conclusion Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn's disease patients exhibiting Paneth cell defects.