Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA

Abstract

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria–localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death–inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics.

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

“…No change was observed in the abundance or activity of the F 1 F 0 ATP synthase or in ANT. The abundance of the PiC was also unaltered but the mitochondrial Pi uptake and Pi-stimulated ATP synthesis were suppressed [46]. Thus, PiC might serve as a target for the effect of viral infection on oxidative phosphorylation.…”

Unexpected role of the phosphate carrier in mitochondrial fragmentation

“…In turn, this results in a disorganization of the actin cytoskeleton and rounding up of the cells, which characterize the CMV-mediated early cytopathic effect. 8 We have recently reported that, similar to Bax, vMIA can stimulate the fragmentation of the mitochondrial network. 13 This is intriguing and counterintuitive because vMIA is a strong inhibitor of apoptosis, 9 while mitochondrial fragmentation is often associated with apoptosis induction.…”

“…viral mitochondrial inhibitor of apoptosis). 8,9 vMIA inhibits apoptosis by recruiting Bax to mitochondria, thereby provoking its inactivation. 10,11 In addition, vMIA is responsible for the early cytopathic effect associated with CMV infection, 8 independently from its interaction with Bax.…”

“…8,9 vMIA inhibits apoptosis by recruiting Bax to mitochondria, thereby provoking its inactivation. 10,11 In addition, vMIA is responsible for the early cytopathic effect associated with CMV infection, 8 independently from its interaction with Bax. 8,12 Moreover, vMIA inhibits the PiC-mediated transport of inorganic phosphate across the inner mitochondrial membrane, thereby reducing ATP synthesis (which is strictly dependent on phosphate import).…”

“…10,11 In addition, vMIA is responsible for the early cytopathic effect associated with CMV infection, 8 independently from its interaction with Bax. 8,12 Moreover, vMIA inhibits the PiC-mediated transport of inorganic phosphate across the inner mitochondrial membrane, thereby reducing ATP synthesis (which is strictly dependent on phosphate import). In turn, this results in a disorganization of the actin cytoskeleton and rounding up of the cells, which characterize the CMV-mediated early cytopathic effect.…”