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MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation

G-T Ho1,2, R E Aird1,3, B Liu4

  • 1MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Mucosal Immunology
|April 13, 2017
PubMed

Insights

The multidrug resistance-1 (MDR1) gene protects mitochondria from damage, preventing colitis. MDR1 deficiency increases mitochondrial reactive oxygen species (mROS), driving inflammatory bowel disease (IBD) development.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • The multidrug resistance-1 (MDR1) gene encodes an efflux transporter highly expressed in the colon.
  • MDR1 deficiency in mice causes colitis, mimicking human inflammatory bowel diseases (IBD).

Purpose of the Study:

  • To investigate the role of MDR1 in mitochondrial function and its connection to colitis development.
  • To explore the link between MDR1, mitochondrial reactive oxygen species (mROS), and IBD pathogenesis.

Main Methods:

  • Mice models with altered MDR1 and SOD2 gene expression were utilized.
  • Mitochondrial function, mROS levels, and colitis development were assessed.
  • Genome-wide association data for IBD susceptibility genes were analyzed.

Main Results:

  • MDR1 deficiency leads to mitochondrial dysfunction and increased mROS, exacerbating colitis.
  • Inhibition of mROS attenuated colitis, while induction accelerated it, especially in MDR1-deficient mice.
  • Human IBD patients showed a negative correlation between MDR1 and SOD2 expression; SOD2 deletion increased colitis susceptibility in mice.
  • A significant portion of IBD susceptibility genes are involved in mitochondrial homeostasis.

Conclusions:

  • MDR1 plays a protective role in mitochondria, preventing colitis by limiting mROS.
  • Mitochondrial dysfunction, driven by a combination of toxins and genetic susceptibility, represents a novel pathogenic mechanism in IBD.
  • These findings suggest new therapeutic strategies targeting mitochondrial pathways for IBD treatment.

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