Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids

Abstract

The link between chronic psychosocial and metabolic stress and the pathogenesis of disease has been extensively documented. Nevertheless, the cellular mechanisms by which stressful life experiences and their associated primary neuroendocrine mediators cause biological damage and increase disease risk remain poorly understood. The allostatic load model of chronic stress focuses on glucocorticoid dysregulation. In this Perspectives, we expand upon the metabolic aspects of this model-particularly glucose imbalance-and propose that mitochondrial dysfunction constitutes an early, modifiable target of chronic stress and stress-related health behaviours. Central to this process is mitochondrial regulation of energy metabolism and cellular signalling. Chronically elevated glucose levels damage both mitochondria and mitochondrial DNA, generating toxic products that can promote systemic inflammation, alter gene expression and hasten cell ageing. Consequently, the concept of 'mitochondrial allostatic load' defines the deleterious structural and functional changes that mitochondria undergo in response to elevated glucose levels and stress-related pathophysiology.

The Cellular Sequelae of Early Stress: Focus on Aging and Mitochondria

“…Similar findings were reported in saliva of subjects with early stress and depression (Cai et al, 2015) and, in animals exposed to chronic stress or depression models, mitochondrial activity is impaired in the hippocampus, thalamus, and cortex (Picard et al, 2014). mtDNA copy number is a gross measure of mitochondrial activity; increases may occur as a compensatory response to impaired mitochondrial function (Picard et al, 2014). These results suggest that early stress may contribute to mechanisms triggering such compensatory responses and that psychiatric disorders may represent a form of chronic stress.…”

“…In the same subjects, telomere length was reduced and mtDNA and telomere length were correlated (Tyrka et al, 2015a). Similar findings were reported in saliva of subjects with early stress and depression (Cai et al, 2015) and, in animals exposed to chronic stress or depression models, mitochondrial activity is impaired in the hippocampus, thalamus, and cortex (Picard et al, 2014). mtDNA copy number is a gross measure of mitochondrial activity; increases may occur as a compensatory response to impaired mitochondrial function (Picard et al, 2014).…”

“…Reactive oxygen species are a by-product of mitochondrial respiration that are not simply mediators of cellular damage but have vital roles in cellular signaling pathways (Picard et al, 2014). Aging is characterized by increased mitochondrial ROS production, declines in mitochondrial function, mtDNA mutation accumulation, and mitochondrial replication alterations.…”

“…Aging is characterized by increased mitochondrial ROS production, declines in mitochondrial function, mtDNA mutation accumulation, and mitochondrial replication alterations. These changes contribute to metabolic and inflammatory system dysregulation and the development of age-related disorders, including diabetes, Alzheimer's disease, and cardiovascular disease (Picard et al, 2014).…”

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

“…It recently has been proposed that mitochondrial allostatic load, the mitochondrial analog of allostatic load in the broader context of stress biology (20), represents a potentially significant pathogenic agent in stress-related disease and cellular aging (21). Mitochondrial allostatic load can be defined as the sum of the potentially damaging changes to mitochondrial structure and function as a consequence of stress exposure.…”