title: Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions.
abstract: Chronic cholestasis is characterized by mitochondrial dysfunction, associated with loss of mitochondrial membrane potential, decreased activities of respiratory chain complexes, and ATP production. Our aim was to determine the molecular mechanisms that link long-term cholestasis to mitochondrial dysfunction. We studied a model of chronic cholestasis induced by bile duct ligation in rats. Key sensors and regulators of the energetic state and mitochondrial biogenesis, mitochondrial DNA (mtDNA)-to-nuclear DNA (nDNA) ratio (mtDNA/nDNA) relative copy number, mtDNA deletions, and indexes of apoptosis (BAX, BCL-2, and cleaved caspase 3) and cell proliferation (PCNA) were evaluated. Our results show that long-term cholestasis is associated with absence of activation of key sensors of the energetic state, evidenced by decreased SIRT1 and pyruvate dehydrogenase kinase levels and lack of AMPK activation. Key mitochondrial biogenesis regulators (PGC-1α and GABP-α) decreased and NRF-1 was not transcriptionally active. Mitochondrial transcription factor A (TFAM) protein levels increased transiently in liver mitochondria at 2 wk after bile duct ligation, but they dramatically decreased at 4 wk. Reduced TFAM levels at this stage were mirrored by a marked decrease (65%) in mtDNA/nDNA relative copy number. The blockade of mitochondrial biogenesis should not be ascribed to activation of apoptosis or inhibition of cell proliferation. Impaired mitochondrial turnover and loss of the DNA stabilizing effect of TFAM are likely the causative event involved in the genetic instability evidenced by accumulation of mtDNA deletions. In conclusion, the lack of stimulation of mitochondrial biogenesis leads to mtDNA severe depletion and deletions in long-term cholestasis. Hence, long-term cholestasis should be considered a secondary mitochondrial hepatopathy.
authors.affiliation: Department of Physiology, University of Valencia, Spain.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Arduini
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
authors.forename: Javier
authors.initials: J
authors.lastname: Escobar
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tormos
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.forename: José
authors.initials: J
authors.lastname: Viña
authors.forename: María
authors.initials: M
authors.lastname: Monsalve
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism; D017353:Gene Deletion; D050259:Genes, Mitochondrial; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D051265:NF-E2-Related Factor 1 / Q000096:biosynthesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D004272:DNA, Mitochondrial; D051268:GA-Binding Protein Transcription Factor; C495649:Gabpa protein, rat; D051265:NF-E2-Related Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; C488368:Sirt1 protein, rat; D056564:Sirtuin 1