General adaptation in critical illness 2: The glucocorticoid signaling system as a master rheostat of homeostatic corrections in concerted action with mitochondrial and essential micronutrient support

Cellular energetics is central to the integrated actions of neuroendocrine and immune responses to stress, while the glucocorticoid signaling system—through its core glucocorticoid (GC) and glucocorticoid receptor alpha (GRα) complex (GC-GRα)—plays a key homeostatic role subserving survival during stressful conditions. The mitochondria play critical roles in energy production during stress and generate signals that promote the adaptive response to stressors, while they are under the control of the GC-GRα complex possibly through GR molecules present within these organelles via glucocorticoid response elements (GRE) residing in the mitochondrial genome. The adaptive homeostatic functions of the activated GC-GRα are, thus, (i) interdependent with mitochondrial biogenesis and adaptation functions and (ii) require reserves of essential micronutrients. A dysregulated systemic inflammation during critical illness is associated with significant damage to the mitochondria, particularly in the cells of highly metabolically active tissues. In potentially lethal cacostasis, critical illness-related corticosteroid insufficiency (CIRCI), mitochondrial dysfunction/injury, and various hypovitaminoses interact to accelerate an antihomeostatic maladaptive process of natural selection. Three vitamins—thiamin, ascorbic acid, and vitamin D—are essential for the proper concerted functions of the glucocorticoid signaling system and the mitochondria, and their reserves are rapidly exhausted in critical illness. Thus, early vitamin supplementation is necessary to allow proper GR-GRα and mitochondrial functions; glucocorticoid and vitamin dosages, timing of administration, and duration of intervention are crucial factors in achieving optimal results in preventing death and long-term morbid sequelae.