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

We found that in the context of pathogenic T cell mediated damage, the Intestinal epithelial cells demonstrated a reduction in OXPHOS and accumulated succinate as a result of decrease in succinate dehydrogenase A, a component of mitochondrial complex II

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 Pennathur; Pavan Reddy

2021

Scholarcy highlights

  • Intestinal epithelial cells function as critical barriers that protect from pathogen invasion.This function is disrupted by environmental factors and/or host genetic factors that cause activation of 47 immune responses that leads to IEC damage and perpetuation of the aberrant inflammation 1 2 3 4
  • Metabolic flux studies, complemented by imaging and protein analyses identified a critical role for IEC intrinsic succinate dehydrogenase A, a component of mitochondrial complex II, in causing these metabolic alterations that contributed to the severity of intestinal damage
  • To analyze complex I function in IECs, we isolated mitochondria from recipients 95 21 d post Hematopoietic cell transplantation and analyzed their ability to oxidize nicotinamide adenine dinucleotide diaphorase to NAD+
  • Analysis of IECs from naïve, syngeneic, and allogeneic recipients post HCT with Blue Native Polyacrylamide Gel Electrophoresis showed alteration of mitochondrial complex II but did not show changes in other mitochondrial supercomplex levels. These results demonstrated that allo-HCT induced changes in mitochondrial electron transport chain and caused disruption of complex II
  • granzyme B caused direct proteolysis of recombinant SDHA but not SDHB demonstrating that the mechanism for reduction of SDHA is because of its proteolysis by GzmB released from the T cells. 384 We evaluated whether the PFN-GzmB dependent cytotoxic pathways is the critical mechanism for in vivo metabolic defect, reduction of SDHA and accumulation of succinate, in the IECs during GVHD and in autoimmune inflammatory bowel diseases
  • The change in O2 levels might lead to dysbiosis with loss of microbial diversity, decrease in commensals such as obligate anaerobes and shift towards to aerobes and pathobionts in the microbiome of patients with GVHD and IBD43 44 45 537 46 47 48 49 50 51 52 53 54 55. 538 539 In summary we identify a novel IEC intrinsic metabolic checkpoint that regulates their sensitivity to T cell mediated cytotoxicity and identify the component of mitochondrial complex II, SDHA, as a potential novel therapeutic target to regulate alloimmune, autoimmune and iatrogenic T cell mediated colitis
  • The critical mechanistic role of Intestinal epithelial cells intrinsic succinate dehydrogenase A was confirmed by complementary chemical and genetic reduction of SDHA and with

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