title: MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation.
abstract: 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 (∼5%) 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.
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.|Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: G-T
authors.initials: GT
authors.lastname: Ho
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.|University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Aird
authors.affiliation: Departments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.|Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Boyapati
authors.affiliation: Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Dorward
authors.affiliation: Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Noble
authors.affiliation: Department of Advanced Aging Medicine, University of Chiba, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: R N
authors.initials: RN
authors.lastname: Carter
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: E T S
authors.initials: ETS
authors.lastname: Chew
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: Departments of Medicine, Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Sartor
authors.affiliation: MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.|University of Bristol, Bristol, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D003092:Colitis / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007422:Intestines / Q000276:immunology*; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2