Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca 2+ 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 Ca 2+ ‐dependent ROS production. The aim of this study was to determine whether core's effects are mediated by changes in mito‐chondrial Ca 2+ uptake. Core expression caused enhanced mitochondrial Ca 2+ uptake in response to ER Ca 2+ 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 Ca 2+ entry rate by ~ 2‐fold. Entry was entirely inhibited by the mitochondrial Ca 2+ uniporter inhibitor, Ru‐360, but not influenced by an Na + /Ca 2+ exchanger inhibitor or ROS scavengers. These results indicate that core directly increases mito‐chondrial Ca 2+ uptake via a primary effect on the uniporter. This enhanced the ability of mitochondria to sequester Ca 2+ in response to ER Ca 2+ release, and increased mitochondrial ROS production and MPT. Thus, the mitochondrial Ca 2+ uniporter is a newly identified target for viral modification of cell function.—Li, Y., Boehning, D. F., Qian, T., Popov, V. L., Weinman, S. A. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca 2+ uniporter activity. FASEB J. 21, 2474–2485 (2007)