Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies

Diaz, F.; Garcia, S.; Hernandez, D.; Regev, A.; Rebelo, A.; Oca-Cossio, J.; Moraes, C. I.
February 2008
Gut;Feb2008, Vol. 57 Issue 2, p232
Academic Journal
Background: Although oxidative phosphorylation defects can affect the liver, these conditions are poorly under- stood, 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 COX1O 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 CDX 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 KB mice survived despite very low COX activity but showed a progressive depletion of glycogen stores. In most animals, hepatocytes that escaped COX1O 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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