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Free Radic Biol Med. 2013 Aug;61:218-28. doi: 10.1016/j.freeradbiomed.2013.04.002. Epub 2013 Apr 16.

Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: Role of the Akt/mTOR survival pathway and Bcl-2 family proteins.

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  • 1Laboratory of Experimental Hepatology and Drug Targeting, (HEVEFARM), IBSAL, CIBERehd; Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain, University of Salamanca, 37007 Salamanca, Spain.
  • 2Laboratory of Experimental Hepatology and Drug Targeting, (HEVEFARM), IBSAL, CIBERehd.
  • 3University Hospital of Salamanca, IECSCYL-IBSAL, 37007 Salamanca, Spain; Department of Biochemistry and Molecular Biology, University of Salamanca, 37007 Salamanca, Spain.
  • 4Laboratory of Experimental Hepatology and Drug Targeting, (HEVEFARM), IBSAL, CIBERehd; University Hospital of Salamanca, IECSCYL-IBSAL, 37007 Salamanca, Spain; Department of Biochemistry and Molecular Biology, University of Salamanca, 37007 Salamanca, Spain. Electronic address: mjperez@usal.es.

Abstract

Acute accumulation of bile acids in hepatocytes may cause cell death. However, during long-term exposure due to prolonged cholestasis, hepatocytes may develop a certain degree of chemoresistance to these compounds. Because mitochondrial adaptation to persistent oxidative stress may be involved in this process, here we have investigated the effects of complete mitochondrial genome depletion on the response to bile acid-induced hepatocellular injury. A subline (Rho) of human hepatoma SK-Hep-1 cells totally depleted of mitochondrial DNA (mtDNA) was obtained, and bile acid-induced concentration-dependent activation of apoptosis/necrosis and survival signaling pathways was studied. In the absence of changes in intracellular ATP content, Rho cells were highly resistant to bile acid-induced apoptosis and partially resistant to bile acid-induced necrosis. In Rho cells, both basal and bile acid-induced generation of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, was decreased. Bile acid-induced proapoptotic signals were also decreased, as evidenced by a reduction in the expression ratios Bax-α/Bcl-2, Bcl-xS/Bcl-2, and Bcl-xS/Bcl-xL. This was mainly due to a downregulation of Bax-α and Bcl-xS. Moreover, in these cells the Akt/mTOR pathway was constitutively activated in a ROS-independent manner and remained similarly activated in the presence of bile acid treatment. In contrast, ERK1/2 activation was constitutively reduced and was not activated by incubation with bile acids. In conclusion, these results suggest that impaired mitochondrial function associated with mtDNA alterations, which may occur in liver cells during prolonged cholestasis, may activate mechanisms of cell survival accounting for an enhanced resistance of hepatocytes to bile acid-induced apoptosis.

Copyright © 2013 Elsevier Inc. All rights reserved.

KEYWORDS:

Akt; Apoptosis; Bcl-2; Bile acid; Cholestasis; Free radicals; Liver; Mitochondria; Retrograde signaling; Rho cells

PMID:
23597504
[PubMed - in process]
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