Bcl-2 family proteins regulate apoptosis by controlling the release of mitochondrial cytochrome c via the Bax/Bak channel. However, recent studies have also implicated several members of this family in the regulation of mitochondrial fission/fusion dynamics. It has been debated whether the role of Bcl-2 proteins in mitochondrial morphogenesis is functionally distinct from their role in apoptosis, with some arguing that Bax/Bak-induced mitochondrial fission promotes apoptosis-associated cytochrome c release, while others suggest that these functions are separable. Here we review this emerging area and argue for a role for the Bcl-2 family as novel regulators of mitochondrial morphogenesis.

We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca2+) concentration in neuroblastoma IMR5 cells, at least partly through Ca2+ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This leads to Ca2+ accumulation in mitochondria through the mitochondrial Ca2+ uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca2+ concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.

Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH 2 -terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.

Poliovirus (PV)-induced apoptosis seems to play a major role in tissue injury in the central nervous system (CNS). We have previously shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. We showed here that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, limiting the extent of JNK activation and thereby cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the apoptosis signal-regulating kinase 1, which acts upstream from JNK in PV-infected IMR5 cells. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in the CNS.Poliovirus (PV), from the Picornaviridae family, causes paralytic poliomyelitis, a disease in which the motor neurons are destroyed in association with PV replication. PV consists of a single-stranded positive-sense RNA genome surrounded by a nonenveloped icosahedral protein capsid. The human PV receptor CD155 and its simian counterparts belong to the immunoglobulin superfamily (24,25,31) and are related to the nectin family of adhesion molecules (28,38).PV is transmitted mostly via the fecal-oral route. It first infects the oropharynx and the digestive tract and then spreads to the central nervous system (CNS), in which it targets mostly motor neurons. Studies with mouse models have shown that PV-infected motor neurons in the spinal cord die by apoptosis (10, 19). PV-induced apoptosis therefore seems to play a major role in the tissue injury occurring in the CNS.PV triggers apoptosis in vitro in tissue cultures of human colon carcinoma (Caco-2) cells (4), promonocytic cells (U937) (29), dendritic cells (41), murine L cells expressing CD155 (21, 36), HeLa cells (8,39), and cultures of mixed mouse primary nerve cells (12) from the cerebral cortexes of mice transgenic for CD155. Analyses of the apoptotic pathways induced following PV infection in several cell lines have demonstrated that mitochondria are key actors of PV-induced apoptosis. In particular, mitochondrial outer membrane permeabilization (MOMP) following PV infection leads to a loss of mitochondrial transmembrane potential and the release of proapoptotic molecules, including cytochrome c, from the mitochondria to the cytosol (8, 21). We recently demonstrated that MOMP in PV-infected neuronal IMR5 cells was dependent on Bax, a proapoptotic member of the Bcl-2 family. Bax activation was mediated by c-Jun NH2-terminal kinase (JNK) phosphorylation after PV infection (6). JNK activation occurred early after PV infection, whereas apoptotic features were observed later in PV-infected cells. These events may involve a balance between pro-and antiapoptotic signals following PV infection. Pro-and antiapoptotic events potentially acting in synergy or competing with each other during the reproduction cycle of PV have been described by Agol's group (1, 39). However, the mechanisms involved in maintaining this delicate balance remain uncle...