Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies.
BACKGROUND
Although oxidative phosphorylation defects can affect the liver, these conditions are poorly understood, partially because of the lack of animal models.


OBJECTIVE
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.
Diaz
F
F
Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA.
Garcia
S
S
Hernandez
D
D
Regev
A
A
Rebelo
A
A
Oca-Cossio
J
J
Moraes
C T
CT
D000367:Age Factors; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D000818:Animals; D030401:Cytochrome-c Oxidase Deficiency / Q000473:pathology; D003576:Electron Transport Complex IV; D017353:Gene Deletion; D022781:Hepatocytes / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000209:etiology / Q000473:pathology*; D010085:Oxidative Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000378:metabolism
D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; C490115:COX10 protein, human; D003576:Electron Transport Complex IV; D019883:Alkyl and Aryl Transferases