Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology

Hideaki Fujiwara, Keisuke Seike, Michael D. Brooks, Anna V. Mathew, Ilya Kovalenko, Anupama Pal, Ho Joon Lee, Daniel Peltier, Stephanie Kim, Chen Liu, Katherine Oravecz-Wilson, Lu Li, Yaping Sun, Jaeman Byun, Yoshinobu Maeda, Max S. Wicha, Thomas L. Saunders, Alnawaz Rehemtulla, Costas A. Lyssiotis, Subramaniam PennathurPavan Reddy

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

Original languageEnglish
Pages (from-to)1440-1451
Number of pages12
JournalNature Immunology
Volume22
Issue number11
DOIs
Publication statusPublished - Nov 2021
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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