期刊
MUCOSAL IMMUNOLOGY
卷 11, 期 1, 页码 120-130出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2017.31
关键词
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类别
资金
- MRC grant [G0701898]
- Crohn's and Colitis UK [M16-1]
- ECCO IBD Investigator's Award
- Chief Scientist Office [ETM/75]
- NIH [P01 DK 094779, R01 DK053347]
- Wellcome Trust Investigator Award [WT100981MA]
- Wellcome Trust [WT096497, WT097943]
- Wellcome Trust Biomedical Vacation Scholarship [202597/Z/16/Z]
- EU FP-7 [305676-2, 305479-2]
- Grants-in-Aid for Scientific Research [26293165] Funding Source: KAKEN
- Chief Scientist Office [ETM/137, ETM/75] Funding Source: researchfish
- Crohn's and Colitis UK [M16-1] Funding Source: researchfish
- Medical Research Council [MR/J003611/1, MC_PC_15049, G0901697, G0401643, G0600033, G0900550, G0701898, G0800759, G0600329, G0800682] Funding Source: researchfish
- Wellcome Trust [100981/Z/13/Z] Funding Source: researchfish
- MRC [G0600033, G0800759, G0800682, G0401643, MR/J003611/1, G0701898, MC_PC_15049, G0901697, G0900550, G0600329] Funding Source: UKRI
- Wellcome Trust [202597/Z/16/Z] Funding Source: Wellcome Trust
The multidrug resistance-1 (MDR1) gene encodes an ATP-dependent efflux transporter that is highly expressed in the colon. In mice, loss of MDR1 function results in colitis with similarities to human inflammatory bowel diseases (IBD). Here, we show that MDR1 has an unexpected protective role for the mitochondria where MDR1 deficiency results in mitochondrial dysfunction with increased mitochondrial reactive oxygen species (mROS) driving the development of colitis. Exogenous induction of mROS accelerates, while inhibition attenuates colitis in vivo; these effects are amplified in MDR1 deficiency. In human IBD, MDR1 is negatively correlated to SOD2 gene expression required for mROS detoxification. To provide direct evidential support, we deleted intestinal SOD2 gene in mice and showed an increased susceptibility to colitis. We exploited the genome-wide association data sets and found many (B5%) of IBD susceptibility genes with direct roles in regulating mitochondria homeostasis. As MDR1 primarily protects against xenotoxins via its efflux function, our findings implicate a distinct mitochondrial toxin + genetic susceptibility interaction leading to mitochondrial dysfunction, a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.
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