Mechanisms of Mitochondrial Redox Signaling in Psychosocial Stress-Responsive Systems: New Insights into an Old Story.

SIGNIFICANCE: Psychosocial stress is associated with alterations in serum glucocorticoids and cytokines, such as interleukin-6 (IL-6) and IL-1β, which functionally interact. However, the molecular mechanisms and physiological relationship between the two systems within the context of stress exposure are not well characterized. Recent Advances: Extracellular IL-6, which stimulates the release of cortisol from the zona fasciculata of the adrenal cortex, mediates its intracellular effects by tyrosine phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3). Mitochondrial electron transfer reactions are involved in both STAT3-driven ATP production in oxidative respiration and adrenocortical steroid biosynthesis. CRITICAL ISSUES: The role of STAT3 in oxidative respiration and steroidogenesis suggests that it integrates both nuclear and mitochondrial actions, thereby preserving main steps of glucocorticoid biosynthesis in the adrenal gland under psychosocial stress. This review discusses the notion that these two pathways are together simultaneously involved in protection against chronic stressors. FUTURE DIRECTIONS: Linking the function of cytokines and main components of the hypothalamic-pituitary-adrenal (HPA) axis to molecular mechanisms of mitochondrial redox signaling will be essential for a better understanding of the relevant stress-responsive systems engaged in stress vulnerability. Antioxid. Redox Signal. 28, 760-772.