Friday, 9 February 2018

An energetic view of stress: Focus on mitochondria

Martin Picard, Bruce S McEwen, Elissa S Epel & Carmen Sandi

In this review, the authors discuss the link between mitochondria and mental stress. 

  • Allostasis is defined as the active (i.e. energy-requiring) process of achieving stability, or homeostasis, through physiological or behavioural change. This includes neuroendocrine, autonomic, epigenetic, metabolic and immune changes, and is generally a short-term adaptation when regulated in a healthy setting.
  • When allostatic mediators are not turned off, these same mediators can cause unhealthy changes in the brain and body: these are the pathophysiological consequences of stress. The authors refer to "allostatic load" as the pathophysiological consequences of chronic dysregulation of allostatic mediators.
  • Metabolic intermediates that are the substrates or co-factors for epigenetic modifications are all derived from the Krebs cycle and other metabolic pathways within mitochondria. Some examples are discussed within the review. Hence, both the addition and removal of epigenetic marks are metabolically/mitochondrially regulated.
  • Mitochondria are the site of synthesis for all steroid hormones, including glucocorticoids such as cortisol (the archetypal stress hormone), androgens such as testosterone and estrogens such as estriol. Norepinephrine and epinephrine are also hormones (called catecholamines) which are released in response to certain stressors. Enzymes involved in the degradation of catecholamines (MAO-A and MAO-B) are anchored to the outer mitochondrial membrane.
  • Glucocorticoids (GCs) increase blood glucose levels by acting on the liver, skeletal muscles and adipose tissue by targetting the glucocorticoid receptor (GR). In the liver, GR activation has been shown to induce chromatin remodelling (an epigenetic effect). In skeletal muscle, GCs antagonize several elements of insulin signalling, and inhibits the uptake of pyruvate by mitochondria.
  • Humans with higher circulating levels of cortisol under resting conditions also have higher levels of glucose, triglycerides and higher insulin resistance (essentially a pre-diabetic state). In mice, chronic GC administration results in glucose intolerance, elevated triglycerides, weight gain and depressive behaviour.
  • Under healthy conditions, GCs are associated with the proper maintainance of a diurnal cycle.
  • Some, but not all, synapses in many parts of the cerebral cortex turn over during the diurnal cycle. Interfering with the daily cycle of GCs can impair motor learning in humans.
  • An animal model of shift work caused dendrites to shrink in the prefrontal cortex and the animal to become cognitively rigid, as well as gaining weight and becoming insulin resistant.

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