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Pathophysiology and Fate of Hepatocytes in a Mouse Model of Mitochondrial Hepatopathies
  1. Francisca Diaz (fdiaz{at}miamiproject.med.miami.edu)
  1. University of Miami, United States
    1. Sofia Garcia (sgarcia{at}miamiproject.med.miami.edu)
    1. University of Miami, United States
      1. Dayami Hernandez (dhernandez{at}miamiproject.med.miami.edu)
      1. University of Miami, United States
        1. Ariel Regev (aregev{at}med.miami.edu)
        1. University of Miami, United States
          1. Adriana Rebelo
          1. University of Miami, United States
            1. Jose Oca-Cossio
            1. University of Florida, United States
              1. Carlos Moraes (cmoraes{at}med.miami.edu)
              1. University of Miami, United States

                Abstract

                Background: Although oxidative phosphorylation defects can affect the liver, these conditions are poorly understood, partially because of the lack of animal models. Aims: To create and characterize the pathophysiology of mitochondrial hepatopathies in a mouse model. Methods: We created a mouse model of mitochondrial hepatopathies by the conditional liver knockout (KO) of the COX10 gene, which is required for cytochrome c oxidase (COX) function. The onset and progression of biochemical, molecular and clinical phenotypes were analyzed in several groups of animals, mostly at days 23, 56, 78 and 155 postnatal. Results: Biochemical and histochemical analysis of liver samples from 23-56 days old KO mice showed liver dysfunction, a severe COX deficiency, marked mitochondrial proliferation and lipid accumulation. Despite these defects, the COX-deficient hepatocytes were not immediately eliminated and apoptosis followed by liver regeneration could be observed only at age 78 days. Hepatocytes from 56-78 days KO mice survived despite very low COX activity but showed a progressive depletion of glycogen stores. In most animals, hepatocytes that escaped COX10 ablation were able to proliferate and completely regenerate the liver between days 78-155. Conclusions: Our results showed that when faced with a severe oxidative phosphorylation defect, hepatocytes in vivo can rely on glycolysis/glycogenolysis for their bioenergetic needs for relatively long periods. Ultimately, defective hepatocytes undergo apoptosis and are replaced by COX-positive cells first observed in the perivascular regions.

                • Mitochondria
                • apoptosis
                • cytochrome oxidase
                • hepatopathy
                • liver

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