FIG. 8.

Diagram summarizing the link between M-MOK binding to Cco1 and aponecrotic activity reported in this study. The CcO complex, located at the inner membrane (IM), in normal conditions catalyzes electron transfer. This is converted to a proton motive force, which subsequently drives ATP synthesis (CcO complex “on”). M produced during MOK infection is transported into the mitochondrial intermembrane space (IS) by passage through the mitochondrial outer membrane. The physical interaction between M and CcO1 decreases CcO activity and mitochondrial oxidative phosphorylation (CcO complex “off”). This event leads to the necrotic component of lyssavirus-induced cell death, essentially by mitochondrial changes and ATP depletion. This response is completed by the extrinsic death receptor-dependent and caspase-dependent pathways, as shown previously (29). The death receptors are synergistically stimulated by death ligands, such as TRAIL, and NO, produced by the mitochondria during lyssavirus infection. If activated by the death-inducing signaling complex (DISC), caspase-8 (C-8) in turn triggers the downstream effector cascade either directly through caspase-3 (C-3) or through engaging the mitochondrial amplification loop. In this process, activated C-8 indirectly triggers cyt-c release and caspase-9 (C-9) activation. This event leads to the apoptotic component of lyssavirus-induced cell death. Thus, in this model, mitochondrial dysfunction plays a key role in M-MOK-mediated cell death.