Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein.
The hepatitis C virus (HCV) core protein is involved in viral pathogenesis such as oxidative stress induction and lipid metabolism disturbance, and is primarily located in the cytoplasm and endoplasmic reticulum in association with lipid droplets as well as in the mitochondria. To clarify the impact of the core protein on mitochondria, we analyzed the expression pattern of mitochondrial proteins in core protein-expressing cells by two-dimensional polyacrylamide gel electrophoresis. Several proteins related to the mitochondrial respiratory chain or protein chaperons were identified by mass spectrometry. Among the identified proteins with consistently different expressions, prohibitin, a mitochondrial protein chaperon, was up-regulated not only in core-expressing cells but also in full-genomic replicon cells and livers of core-gene transgenic mice. The stability of prohibitin was increased through interaction with the core protein. Further analysis demonstrated that interaction of prohibitin with mitochondrial DNA-encoded subunits of cytochrome c oxidase (COX) was disturbed by the core protein, resulting in a significant decrease in COX activity.


CONCLUSIONS
The HCV core protein affects the steady-state levels of a subset of mitochondrial proteins including prohibitin, which may lead to an impaired function of the mitochondrial respiratory chain with the overproduction of oxidative stress.
Tsutsumi
Takeya
T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Japan.
Matsuda
Mami
M
Aizaki
Hideki
H
Moriya
Kyoji
K
Miyoshi
Hideyuki
H
Fujie
Hajime
H
Shintani
Yoshizumi
Y
Yotsuyanagi
Hiroshi
H
Miyamura
Tatsuo
T
Suzuki
Tetsuro
T
Koike
Kazuhiko
K
D000818:Animals; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D000091402:Prohibitins; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000378:metabolism*
D018832:Molecular Chaperones; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D003576:Electron Transport Complex IV