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

Francisca Diaz, S. Garcia, D. Hernandez, A. Regev, A. Rebelo, J. Oca-Cossio, Carlos T Moraes

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)232-242
Number of pages11
JournalGut
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2008

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Hepatocytes
Oxidoreductases
Liver
Oxidative Phosphorylation
Knockout Mice
Apoptosis
Glycogenolysis
Gene Knockout Techniques
Liver Regeneration
Glycolysis
Electron Transport Complex IV
Glycogen
Energy Metabolism
Liver Diseases
Animal Models
Phenotype
Lipids

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. / Diaz, Francisca; Garcia, S.; Hernandez, D.; Regev, A.; Rebelo, A.; Oca-Cossio, J.; Moraes, Carlos T.

In: Gut, Vol. 57, No. 2, 01.02.2008, p. 232-242.

Research output: Contribution to journalArticle

Diaz, F, Garcia, S, Hernandez, D, Regev, A, Rebelo, A, Oca-Cossio, J & Moraes, CT 2008, 'Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies', Gut, vol. 57, no. 2, pp. 232-242. https://doi.org/10.1136/gut.2006.119180
Diaz F, Garcia S, Hernandez D, Regev A, Rebelo A, Oca-Cossio J et al. Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. Gut. 2008 Feb 1;57(2):232-242. https://doi.org/10.1136/gut.2006.119180
Diaz, Francisca ; Garcia, S. ; Hernandez, D. ; Regev, A. ; Rebelo, A. ; Oca-Cossio, J. ; Moraes, Carlos T. / Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. In: Gut. 2008 ; Vol. 57, No. 2. pp. 232-242.
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