Bax and B-cell-lymphoma 2 mediate proapoptotic signaling following chronic isolation stress in rat brain

Mitochondrial dysfunction has been implicated in several psychiatric disorders, including depression. Given that the B-cell-lymphoma 2 (Bcl-2) protein family plays a role in the regulation of mitochondrial apoptotic pathway, we hypothesized that ratio of proapoptotic to antiapoptotic proteins (e.g., Bcl-2-associated X protein (Bax)/Bcl-2) may determine prosurvival/proapoptotic intracellular signaling under stress. We tested this hypothesis by examining the effects of 2 h of acute stress immobilization (IM) or cold (C), 21 days of social isolation as chronic stress and combined stress (chronic stress followed by acute stress) on cytosolic/mitochondrial levels and ratios of Bax and Bcl-2 proteins in relation to cytosolic nitric oxide (NO) metabolites (nitrates and nitrites) and p53 protein redistribution between cytosolic and mitochondrial compartments in the prefrontal cortex (PFC) and hippocampus (HIPP) of male Wistar rats. The stress-induced changes in serum corticosterone (CORT) concentrations were also followed. Acute stressors resulting in an elevated CORT level did not change the Bax/Bcl-2 ratio in either brain region. However, chronic isolation, resulting in CORT levels similar to basal values, led to a translocation of mitochondrial Bcl-2 to the cytosol in the PFC. Furthermore, the Bax/Bcl-2 ratio in the PFC was significantly increased following chronic isolation and remained elevated after combined stressors. NO metabolites were increased by chronic isolation and the two combined stressors in the HIPP and following the combined stressors in the PFC. Translocation of p53 and proapoptotic Bax from the cytosol into mitochondria in response to NO overproduction following combined stressors was detected only in the PFC. These data indicate that chronic isolation stress exerts opposing actions on p53 and NO mechanisms in a tissue-specific manner (PFC vs. HIPP), triggering proapoptotic signaling via Bcl-2 translocation in the PFC.

► Chronic isolation stress initiates mitochondrial proapoptotic pathway.
► Chronic isolation stress deregulates HPA axis activity judging by CORT levels.
► Bcl-2 cytosolic translocation in the PFC triggers proapoptotic signaling.
► NO-induced p53 and Bax mitochondrial translocation augment proapoptotic events.
► PFC is the key target of the maladaptive response to chronic isolation stress.