Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity.
Many viruses have evolved mechanisms to alter mitochondrial function. The hepatitis C virus (HCV) produces a viral core protein that targets to mitochondria and increases Ca2+-dependent ROS production. The aim of this study was to determine whether core's effects are mediated by changes in mitochondrial Ca2+ uptake. Core expression caused enhanced mitochondrial Ca2+ uptake in response to ER Ca2+ release induced by thapsigargin or ATP. It also increased mitochondrial superoxide production and mitochondrial permeability transition (MPT). Incubating mouse liver mitochondria with an HCV core (100 ng/mg) in vitro increased Ca2+ entry rate by approximately 2-fold. Entry was entirely inhibited by the mitochondrial Ca2+ uniporter inhibitor, Ru-360, but not influenced by an Na+/Ca2+ exchanger inhibitor or ROS scavengers. These results indicate that core directly increases mitochondrial Ca2+ uptake via a primary effect on the uniporter. This enhanced the ability of mitochondria to sequester Ca2+ in response to ER Ca2+ release, and increased mitochondrial ROS production and MPT. Thus, the mitochondrial Ca2+ uniporter is a newly identified target for viral modification of cell function.
Li
Yanchun
Y
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0620, USA.
Boehning
Darren F
DF
Qian
Ting
T
Popov
Vsevolod L
VL
Weinman
Steven A
SA
D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D002118:Calcium / Q000502:physiology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D018936:Hepatitis C Antigens / Q000494:pharmacology*; D006801:Humans; D008099:Liver; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014758:Viral Core Proteins / Q000494:pharmacology*
D017920:Antiporters; D027682:Cation Transport Proteins; D018936:Hepatitis C Antigens; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014758:Viral Core Proteins; C027614:calcium-hydrogen antiporters; D002118:Calcium