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Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca²⁺ uniporter activity

Yanchun Li^*, Darren F. Boehning^*, Ting Qian^*, Vsevolod L. Popov and Steven A. Weinman^*,,1

Departments of
^* Neuroscience and Cell Biology,

Pathology, and

Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA

¹Correspondence: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0620, USA. E-mail: sweinman{at}utmb.edu

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 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, Y., Boehning, D. F., Qian, T., Popov, V. L., Weinman. S. A. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca²⁺ uniporter activity.

Key Words: HCV core • mitochondria • cytosolic Ca²⁺ • MAVS