Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Abstract

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein 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.