Open AccessMitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology
Author(s) -
Hideaki Fujiwara,
Keisuke Seike,
Michael Brooks,
Anna V. Mathew,
Ilya Kovalenko,
Anupama Pal,
HoJoon Lee,
Daniel Peltier,
Stephanie Kim,
Chen Liu,
Katherine Oravecz-Wilson,
Lü Li,
Yaping Sun,
Jaeman Byun,
Yoshinobu Maeda,
Max S. Wicha,
Thomas L. Saunders,
Alnawaz Rehemtulla,
Costas A. Lyssiotis,
Subramaniam Pennathur,
Pavan Reddy
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-01048-3
Subject(s) - sdha , biology , colitis , microbiology and biotechnology , immune system , inflammatory bowel disease , mitochondrion , immunology , oxidative phosphorylation , mitochondrial disease , succinate dehydrogenase , cancer research , disease , medicine , mitochondrial dna , pathology , biochemistry , gene
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.