title: Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis.
abstract: OBJECTIVE
  We have reported the involvement of deregulated autophagy and subsequent cellular senescence in biliary epithelial lesions in primary biliary cirrhosis (PBC). Given that mitochondria are a major target of autophagy, we hypothesized that deregulated autophagy of mitochondria may be involved in autoimmune pathogenesis in PBC.
  
  
  METHODS
  We examined immunohistochemically the expression of pyruvate dehydrogenase complex-E2 component (PDC-E2) and cytochrome c oxidase, subunit I (CCO), in livers taken from patients with PBC (n = 42) and control livers (n = 76). The colocalization of mitochondrial antigens with an autophagy marker microtubule-associated protein-light chain 3β (LC3), a deregulated autophagy marker p62/sequestosome-1 (p62) and a lysosomal marker LAMP-1 was examined by double immunofluorescence. We examined the colocalization of mitochondrial antigens with LC3, p62 and LAMP-1 and the cell-surface expression of PDC-E2 in cultured biliary epithelial cells (BECs) treated with various stresses.
  
  
  RESULTS
  Intense granular expression of PDC-E2 and CCO was seen in the damaged small bile ducts (SBDs) in PBC and the expression was significantly more frequent in PBC than in control livers (P < 0.01). The granular expression of mitochondrial antigens was colocalized with LC3 in damaged SBDs in PBC. The accumulation of LC3-expressing punctae colocalized with PDC-E2 and CCO was significantly more increased in cultured BECs treated with various stresses. The cell-surface expression of PDC-E2 was induced by various stresses in BECs.
  
  
  CONCLUSIONS
  Deregulated autophagy may contribute to the abnormal expression of mitochondrial antigens and may be involved in the autoimmune pathogenesis of bile duct lesions in PBC.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masami
authors.initials: M
authors.lastname: Miyakoshi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000503:physiopathology*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D024101:Mitochondrial Proteins / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D003576:Electron Transport Complex IV; D051907:Lysosomal Membrane Proteins; D024101:Mitochondrial Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1