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J. Biol. Chem., Vol. 279, Issue 15, 15460-15471, April 9, 2004

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Human Hepatitis B Virus-X Protein Alters Mitochondrial Function and Physiology in Human Liver Cells^*

Young Ik Lee, Jung Me Hwang, Jee Hye Im, Yoon Ik Lee, Nam Soon Kim, Dae Gon Kim, Dae Yeul Yu¶, Hyung Bae Moon||, and Sook Kyung Park

From the Liver Cell Signal Transduction Laboratory and the ^¶Development and Differentiation Laboratory, Bioscience Research Division, Korea Research Institute of Bioscience and Biotechnology, P. O. Box 115, Yusong, Taejon 305-600, the ^||Department of Pathology, Wonkwang Medical School, Wonkwang University, Iksan, Chonbook 570-749, and the Division of Gastroenterology and Hepatology, Chonbook National University, Chonju, Chonbook 561-756, Korea

The hepatitis B virus-X protein (HBx) regulates fundamental aspects of mitochondrial physiology. We show that HBx down-regulates mitochondrial enzymes involved in electron transport in oxidative phosphorylation (complexes I, III, IV, and V) and sensitizes the mitochondrial membrane potential in a hepatoma cell line. HBx also increases the level of mitochondrial reactive oxygen species and lipid peroxide production. HBx does not activate apoptotic signaling, although it sensitizes hepatoma cells to apoptotic signaling, which is dependent on reactive oxygen species. Increased intrahepatic lipid peroxidation in HBx transgenic mice demonstrated that oxidative injury occurs as a direct result of HBx expression. Therefore, we conclude that mitochondrial dysfunction is a crucial pathophysiological factor in HBx-expressing hepatoma cells and provides an experimental rationale in the investigation of mitochondrial function in rapidly renewed tissues, as in hepatocellular carcinomas.

Received for publication, August 21, 2003 , and in revised form, January 5, 2004.

^* This work was supported by Korean Science and Engineering Foundation Science Research Center Fund Grants MTR 00-1-1 and OGM0100311. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 82-42-860-4150; Fax: 82-42-860-4597; E-mail: yilee{at}mail.kribb.re.kr.

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