Protection against Hepatocyte Mitochondrial Dysfunction Delays Fibrosis Progression in Mice

Claudia Mitchell^*, Marie-Anne Robin, Alicia Mayeuf^*, Meriem Mahrouf-Yorgov^*, Abdellah Mansouri, Marie Hamard^*, Dominique Couton^*, Bernard Fromenty and Hélène Gilgenkrantz^*

From the Institut Cochin,^* Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), Paris; INSERM, U567, Paris; INSERM, U620, Université de Rennes 1, Rennes; and INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris, France

Accumulating evidence indicates that oxidative stress is involvedin the physiopathology of liver fibrogenesis. However, amidthe global context of hepatic oxidative stress, the specificrole of hepatocyte mitochondrial dysfunction in the fibrogenicprocess is still unknown. The aim of this study was to determinewhether a targeted protection of hepatocytes against mitochondrialdysfunction could modulate fibrosis progression. We inducedliver fibrogenesis by chronic carbon tetrachloride treatment(3 or 6 weeks of biweekly injections) in transgenic mice expressingBcl-2 in their hepatocytes or in normal control mice. Analysesof mitochondrial DNA, respiratory chain complexes, and lipidperoxidation showed that Bcl-2 transgenic animals were protectedagainst mitochondrial dysfunction and oxidative stress resultingfrom carbon tetrachloride injury. Picrosirius red staining, ${alpha}$ -smooth muscle actin immunohistochemistry, and real-time PCRfor transforming growth factor-β and collagen ${alpha}$ -I revealedthat Bcl-2 transgenic mice presented reduced fibrosis at earlystages of fibrogenesis. However, at later stages increased nonmitochondrial/nonhepatocyticoxidative stress eventually overcame the capacity of Bcl-2 overexpressionto prevent the fibrotic process. In conclusion, we demonstratefor the first time that specific protection against hepatocytemitochondrial dysfunction plays a preventive role in early stagesof fibrogenesis, delaying its onset. However, with the persistenceof the aggression, this protection is no longer sufficient toimpede fibrosis progression.