Mitochondrial biogenesis fails in secondary biliary cirrhosis in XXXX leading to mitochondrial DNA depletion and deletions.

@entity72630 @entity15412 @entity1976 @entity2310 @entity6229 @entity34810 @entity1448 @entity19310 @entity35 @entity2388 @entity855 @entity2383
@entity1448 is characterized by @entity2383 , associated with loss of mitochondrial membrane potential, decreased activities of respiratory chain complexes, and @entity855 production. Our aim was to determine the molecular mechanisms that link long-term @entity1448 to @entity2383 . We studied a model of chronic @entity1448 induced by bile duct ligation in @entity35 . 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 ( @entity2310 , @entity1976 , and cleaved caspase 3) and cell proliferation (PCNA) were evaluated. Our results show that long-term @entity1448 is associated with absence of activation of key sensors of the energetic state, evidenced by decreased @entity19310 and @entity2388 dehydrogenase kinase levels and lack of AMPK activation. Key mitochondrial biogenesis regulators ( @entity6229 and @entity72630 ) decreased and @entity34810 was not transcriptionally active. Mitochondrial transcription factor A ( @entity15412 ) protein levels increased transiently in liver mitochondria at 2 wk after bile duct ligation, but they dramatically decreased at 4 wk. Reduced @entity15412 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. @entity2383 and loss of the DNA stabilizing effect of @entity15412 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 @entity1448 . Hence, long-term @entity1448 should be considered a secondary mitochondrial hepatopathy.
