Navarro S1, del Hoyo P1, Campos Y1, Abitbol M2, Morán-Jiménez MJ1, GarcÃa-Bravo M1, Grau M1, Montagutelli X2, EnrÃquez de Salamanca R1, Fontanellas A1
1Centro de Investigación, Hospital 12 de Octubre, Madrid, Spain, 2Unité de Génétique des Mammiferes, Institut Pasteur, Paris, France
The Fechm1pas/Fechm1pas murine model for erythropoietic protoporphyria (EPP) affords an excellent system with which to investigate the pathogenesis of severe protoporphyria-induced liver failure. The aim of this study was to identify factors involved in the development of this type of hepatic disease. Interestingly, mice from different strains congenic for the same ferrochelatase germline mutation manifest variable degrees of hepatobiliary injury. Protoporphyric animals bred into the C57BL/6J background showed a higher degree of hepatomegaly and liver damage as well as higher protoporphyrin accumulation than those bred into the SJL/J and BALB/cJ backgrounds. Mitochondrial respiratory chain (MRC) activities remained unchanged in the liver of C57BL/6J mice, whereas they were increased in protoporphyric mice from both SJL/J and BALB/cJ backgrounds. However, no alterations of MRC activities were detectable in spleen, kidney and bone marrow from EPP mice. MRC activities were increased in Hep G2 cell lines after accumulation of protoporphyrin following addition of delta-aminolevulinic acid. As a direct effect of these elevated MRC activities, in both hepatic cells from mutant mouse strains and Hep G2 cell lines, ATP levels significantly increased as the intracellular protoporphyrin concentration was reduced. In conclusion, these results indicate that the cytotoxic effects of protoporphyrin accumulation in the liver may be counterbalanced by increases in ATP suggesting that increased MRC activities protect against hepatocellular injury in EPP mice. It may prove helpful to assess MRC activities as an approach to identifying that subset of EPP patients at risk for developing severe liver injury.