TY - JOUR
T1 - Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology
AU - Fujiwara, Hideaki
AU - Seike, Keisuke
AU - Brooks, Michael D.
AU - Mathew, Anna V.
AU - Kovalenko, Ilya
AU - Pal, Anupama
AU - Lee, Ho Joon
AU - Peltier, Daniel
AU - Kim, Stephanie
AU - Liu, Chen
AU - Oravecz-Wilson, Katherine
AU - Li, Lu
AU - Sun, Yaping
AU - Byun, Jaeman
AU - Maeda, Yoshinobu
AU - Wicha, Max S.
AU - Saunders, Thomas L.
AU - Rehemtulla, Alnawaz
AU - Lyssiotis, Costas A.
AU - Pennathur, Subramaniam
AU - Reddy, Pavan
N1 - Funding Information:
This work was supported by US NIH grants HL090775, CA173878, CA203542, HL149633 (to P.R.), K08HL130944 (to A.V.M.), DK081943 and DK89503 (to S.P.), JSPS Postdoctoral Fellowships for Research Abroad (to H.F.), The YASUDA Medical Foundation Grants for Research Abroad (to H.F.), JSPS KAKENHI grants JP20K22901 and JP21H02904 (to H.F.), The Kawasaki Foundation of Medical Science and Medical Welfare (to H.F.), The Ryobiteien Memorial Foundation (to H.F.), The MSD Life Science Foundation Public Interest Incorporated Foundation (to H.F.), The Okayama Medical Foundation (to H.F.), The SENSHIN Medical Research Foundation (to H.F.), The Kato Memorial Bioscience Foundation (to H.F.) and The NOVARTIS Foundation (Japan) for the Promotion of Science (to H.F.). We acknowledge use of the Microscopy & Image-analysis Laboratory (MIL) of the University of Michigan’s Biomedical Research Core Facilities for the preparation of samples and images. Support for the MIL core is provided by the University of Michigan Rogel Cancer Center (NIH grant CA46592).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-021-01048-3
DO - 10.1038/s41590-021-01048-3
M3 - Article
C2 - 34686860
AN - SCOPUS:85117449565
SN - 1529-2908
VL - 22
SP - 1440
EP - 1451
JO - Nature Immunology
JF - Nature Immunology
IS - 11
ER -
