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Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids

Nature Reviews Endocrinology volume 10, pages 303–310 (2014)Cite this article

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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.

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Figure 1: The stress–disease cascade and mitochondrial allostatic load.
Figure 2: Hypothetical model demonstrating how sustained lifestyle and behaviour modulate adaptive capacity.
Figure 3: Mitochondrial allostatic load and downstream biological effects.

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Authors and Affiliations

  1. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania, 3501 Civic Center Boulevard, Philadelphia, 19104, PA, USA

    Martin Picard

  2. Integrated Program in Neuroscience, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, H3A 2B4, QC, Canada

    Robert-Paul Juster

  3. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, 10065, NY, USA

    Bruce S. McEwen

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M.P. researched the data for the article. All authors provided a substantial contribution to discussions of the content, contributed to writing the article and reviewed and/or edited the manuscript before submission.

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Picard, M., Juster, RP. & McEwen, B. Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids. Nat Rev Endocrinol 10, 303–310 (2014). https://doi.org/10.1038/nrendo.2014.22

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