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

Dakota N. Jackson, Marina Panopoulos, William L. Neumann, Kevin Turner, Brandi Cantarel, Luann Thompson-Snipes, Themistocles Dassopoulos, Linda A Feagins, Rhonda F. Souza, Jason C. Mills, Richard S. Blumberg, K. Venuprasad, Winston E. Thompson, Arianne L. Theiss

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Objective 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 iΔIEC) or Paneth cell-specific deletion of Phb1 (Phb1 ΔPC) 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 iΔIEC or Phb1 ΔPC mice. Results Phb1 iΔIEC 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 iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1 ΔPC) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1 iΔIEC or Phb1 ΔPC 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.

Original languageEnglish (US)
Pages (from-to)1928-1938
Number of pages11
Issue number11
StatePublished - Nov 1 2020


  • Crohn's disease
  • epithelial cells
  • inflammatory bowel disease

ASJC Scopus subject areas

  • Gastroenterology


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