Genetic Defects in ER Stress and Autophagy Translate Into Increased Functional ER Stress Levels in Patients with Inflammatory Bowel Disease

current GWA datasets (42,992 IBD/53,536 controls) to determine the clinical significance of mitochondrial homoestasis in IBD.Results: Damaged mitochondria accumulate in mdr1a-/-CECs vs. ileum/liver/lung; and vs. WT and il-10-/-CECs.Mdr1a-/-CECs have increased expression of p62, LC3 (general autophagy), PINK (specific mitophagy) and SOD2 protein expressions and impaired cellular energetics with reduced baseline respiration.Isolated Mdr1a-/-mitochondria have lower threshold to induced damage and produced more mtROS, which are replicated in vitro in T84 shMDR1 CECs.In vivo, colonic rotenone acccelerated spontaneous mdr1a-/-colitis, increased the severity of acute DSS-colitis in mdr1a-/-and in WT mice.Inhibition of mROS using MitoQ 10 attenuated the severity and promoted the recovery from DSS colitis.SOD2-IEC∆ mice displayed analagous dysmorphic mitochondria in CECs and are highly susceptible to DSS colitis.We showed that 29 (5.0%) of 574 IBD susceptibility genes (p<5 x 10 -8) have direct roles in mitochondria function (GO term:0005739).MDR1 and SOD2 genes showed associations with p=3.19 x 10 -3 and 3.04 x 10 -3 respectively.Conclusions: MDR1 has an important protective role for the mitochondria in the colon.Given that many IBD susceptibility genes are involved in the regulation of mitochondrial health, our findings suggest that mitochondrial toxin + genetic susceptibility interaction leading to mitochondrial dysfunction is a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.MtROS-mitochondrial reactive species, CECs -colonic epithelial cells, WT-wild-type Tu1768