Characterization of the Mitochondrial Phenotype Associated with Primary Biliary Cholangitis

• Author / Creator

  Wysokinski, Filip

• Primary Biliary Cholangitis (PBC) is a chronic liver disease characterized by the immune-mediated destruction of intra-hepatic bile ducts. The autoimmune nature of PBC involves humoral and cell-mediated responses that target endogenous mitochondrial proteins. It is thought that the breakdown of immune tolerance relates to the aberrant localization of mitochondrial proteins to the cell surface of PBC patient bile ducts. Mitochondrial dysfunction, altered expression of metabolic regulators, and modified redox homeostasis have also been implicated in disease pathogenesis; however, exactly how these processes relate to the pathogenesis of PBC remains unclear. Here we have characterized metabolic and mitochondrial function in PBC patients’ cultured biliary epithelial cells (BEC) relative to liver disease controls. Shotgun-proteomics of cultured BEC illustrated elevated expression of enzymes related to aerobic glycolysis, fatty acid degradation, the mitochondrial compartment and redox homeostasis. Subsequent, functional assays revealed that both aerobic glycolysis and mitochondrial respiration are elevated in PBC BEC in vitro. Elevated levels of mtDNA copy number are also observed in PBC BEC. These studies support that PBC BEC show a novel phenotype with metabolic and mitochondrial changes, which may be related to disease pathogenesis. Given that mitochondrial function plays critical roles in both cellular viability and immunity, further work dissecting this phenotype in PBC may provide novel insight into disease pathogenesis and illustrate future targets for therapeutic intervention.

• Subjects / Keywords

  • Liver Disease
  • Cholangiocyte
  • Proteomics
  • Cholestasis
  • Glycolysis
  • Primary Biliary Cholangitis
  • Metabolism
  • Mitochondria
  • Bile Duct
  • Oxidative Phosphorylation

• Graduation date

  Spring 2017

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R33X83Z3C

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.