Box 2 | Stress-induced mitochondrial dysfunction and psychiatric disorders

From the following article:

Impaired mitochondrial function in psychiatric disorders

Husseini Manji, Tadafumi Kato, Nicholas A. Di Prospero, Seth Ness, M. Flint Beal, Michael Krams & Guang Chen

Nature Reviews Neuroscience 13, 293-307 (May 2012)

doi:10.1038/nrn3229

Social–psychological and physical stress are considered to be common contributory factors to many neuropsychiatric illnesses. In humans and laboratory animals, stress increases levels of glucocorticoids, both in the CNS and peripherally175. Accumulating data show that glucocorticoids bound to glucocorticoid receptors not only regulate gene expression in the cell nucleus176 but can also translocate to mitochondria and regulate mitochondrial gene expression176. This mitochondrial translocation is mediated, at least in part, by B-cell lymphoma protein 2 (BCL-2)176. Furthermore, acute exposure of cultured neurons to either low or high levels of glucocorticoids enhances mitochondrial function — including increases in membrane potentials, calcium-holding capacity and oxidation — whereas chronic exposure of neurons to high glucocorticoid levels, which can occur after stress, impairs mitochondrial function176. These data suggest a possible mitochondrial link between chronic stress and psychiatric and neurodegenerative disorders.

Stress also increases levels of pro-inflammatory cytokines (for example, interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α) in the CNS and peripherally175, and there is mounting evidence to implicate the activation of pro-inflammatory cascades in the pathophysiology of major depressive disorder177. Notably, cytokines can induce activation of anti-apoptotic, as well as pro-apoptotic, members of the BCL-2 family13, 176 and can also affect mitochondrial function through intracellular signalling pathways176. However, further studies are needed to determine whether the effects of cytokines on mitochondrial function are directly involved in the induction of mood-disorder-related behavioural alterations, collateral change, or both.