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Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies
  1. F Diaz1,
  2. S Garcia1,
  3. D Hernandez1,
  4. A Regev2,
  5. A Rebelo3,
  6. J Oca-Cossio4,
  7. C T Moraes1,3
  1. 1
    Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA
  2. 2
    Department of Medicine, Division of Hepatology, Center for Liver Diseases, University of Miami, Miller School of Medicine, Miami, FL, USA
  3. 3
    Department of Cell Biology and Anatomy, University of Miami, Miller School of Medicine, Miami, FL, USA
  4. 4
    Department of Medicine, Division of Endocrinology, University of Florida, Gainesville, FL, USA
  1. Professor Carlos T Moraes, 1095 NW 14th Terrace, Miami, FL 33136, USA; cmoraes{at}


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 characterise the pathophysiology of mitochondrial hepatopathies in a mouse model.

Methods: A mouse model of mitochondrial hepatopathies was created 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 analysed in several groups of animals, mostly at postnatal days 23, 56, 78 and 155.

Results: Biochemical and histochemical analysis of liver samples from 23–56-day-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-day-old 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 and 155.

Conclusions: The 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.

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