Figure 1. Stress-induced damage to mitochondrial function and neurotransmitter signaling in the pathophysiology of PTSD, depression, and suicidal ideation.

Chronic stress and sleep deprivation increase cortisol (which binds to its receptor, glucocorticoid receptor, GR) and corticotrophin releasing factor (CRF), followed by enhanced oxidative stress and higher homocysteine levels, which subsequently lead to mitochondrial dysfunction and lipid degradation in the neurons in the circuits mediating cognitive, affective, motoric, and neurovegetative functions. In addition, it was reported that chronic stress lead to down-regulation of neurotrophic factor brain-derived neurotrophic factor (BDNF) expression, which may also contribute to the chronic stress-induced neuronal damage. Chronic stress also increases intracellular glutamate levels, which may cause altered calcium signaling and oxidative stress in the neurons. Glial cells include the astrocytes, oligodendrocytes, and microglia. Tripartite synapse represents the pre-synaptic structure, the post-synaptic structure and the surrounding astrocyte as a functional unit. Astrocytes sense and regulate synaptic activity depending on intracellular Ca²⁺ levels. Mitochondria provide trophic support, energy, and calcium-buffering capacity in the neuronal cell body, the astrocytes, the dendrites, and the synapses. Mitochondrial dysfunction and altered lipid rafts may lead to aberrant neurotransmitter signaling, dendritic atrophy, and neuronal endangerment. This stress-induced neuronal damage interacts with genetic and environmental factors, including adverse childhood events, exposure to trauma, drug abuse, smoking, alcohol use, sleep, diet, and exercise levels to eventually precipitate mental illness in vulnerable individuals. Depending on the severity of these factors, and an individual’s personal predisposition, the course of the illness may develop towards a variety of psychiatric disorders.