Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Emerging Risk Factors Collaboration et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).

  2. Olshansky, S. J. et al. A potential decline in life expectancy in the United States in the 21st century. N. Engl. J. Med 352, 1138–1145 (2005).

    CAS  PubMed  Google Scholar 

  3. van Elderen, S. G. et al. Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 75, 997–1002 (2010).

    CAS  PubMed  Google Scholar 

  4. Mattson, M. P. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 16, 706–722 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Dallman, M. F. et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 14, 303–347 (1993).

    CAS  PubMed  Google Scholar 

  6. Dickerson, S. S. & Kemeny, M. E. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol. Bull. 130, 355–391 (2004).

    PubMed  Google Scholar 

  7. Testa, R. et al. Leukocyte telomere length is associated with complications of type 2 diabetes mellitus. Diabet. Med. 28, 1388–1394 (2011).

    CAS  PubMed  Google Scholar 

  8. Epel, E. S. et al. Accelerated telomere shortening in response to life stress. Proc. Natl Acad. Sci. USA 101, 17312–17315 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Shalev, I. et al. Stress and telomere biology: a lifespan perspective. Psychoneuroendocrinology 38, 1835–1842 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Picard, M. Pathways to aging: the mitochondrion at the intersection of biological and psychosocial sciences. J. Aging Res. 2011, 814096 (2011).

    PubMed  PubMed Central  Google Scholar 

  11. McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

    PubMed  Google Scholar 

  12. McEwen, B. S. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin. Neurosci. 8, 367–381 (2006).

    PubMed  PubMed Central  Google Scholar 

  13. Cohen, S., Janicki-Deverts, D. & Miller, G. E. Psychological stress and disease. JAMA 298, 1685–1687 (2007).

    CAS  PubMed  Google Scholar 

  14. McEwen, B. S. Brain on stress: how the social environment gets under the skin. Proc. Natl Acad. Sci. USA 109 (Suppl. 2), 17180–17185 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10, 434–445 (2009).

    CAS  PubMed  Google Scholar 

  16. Steptoe, A. & Kivimäki, M. Stress and cardiovascular disease: an update on current knowledge. Annu. Rev. Public Health 34, 337–354 (2013).

    PubMed  Google Scholar 

  17. Sinha, R. & Jastreboff, A. M. Stress as a common risk factor for obesity and addiction. Biol. Psychiatry 73, 827–835 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Puterman, E. & Epel, E. An intricate dance: life experience, multisystem resiliency, and rate of telomere decline throughout the lifespan. Soc. Personal Psychol. Compass. 6, 807–825 (2012).

    PubMed  PubMed Central  Google Scholar 

  19. Shalev, I. et al. Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol. Psychiatry 18, 576–581 (2013).

    CAS  PubMed  Google Scholar 

  20. Steptoe, A. et al. Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women. Brain Behav. Immun. 25, 1292–1298 (2011).

    PubMed  Google Scholar 

  21. Tomiyama, A. J. et al. Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length. Physiol. Behav. 106, 40–45 (2012).

    CAS  PubMed  Google Scholar 

  22. Puterman, E. et al. The power of exercise: buffering the effect of chronic stress on telomere length. PLoS ONE 5, e10837 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Sterling, P. & Eyer, J. in Handbook of Life Stress, Cognition and Health (eds. Fisher, S. & Reason, J.) 629–649 (John Wiley & Sons, New York, 1988).

    Google Scholar 

  24. Stumvoll, M., Tataranni, P. A., Stefan, N., Vozarova, B. & Bogardus, C. Glucose allostasis. Diabetes 52, 903–909 (2003).

    CAS  PubMed  Google Scholar 

  25. McEwen, B. S. Protective and damaging effects of stress mediators. N. Engl. J. Med. 338, 171–179 (1998).

    CAS  PubMed  Google Scholar 

  26. McEwen, B. S. & Stellar, E. Stress and the individual. Mechanisms leading to disease. Arch. Intern. Med. 153, 2093–2101 (1993).

    CAS  PubMed  Google Scholar 

  27. Juster, R. P. et al. A transdisciplinary perspective of chronic stress in relation to psychopathology throughout lifespan development. Dev. Psychopathol. 23, 725–776 (2011).

    PubMed  Google Scholar 

  28. Juster, R. P., McEwen, B. S. & Lupien, S. J. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci. Biobehav. Rev. 35, 2–16 (2010).

    PubMed  Google Scholar 

  29. Seeman, T. E., McEwen, B. S., Rowe, J. W. & Singer, B. H. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc. Natl Acad. Sci. USA 98, 4770–4775 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Andrews, R. C. & Walker, B. R. Glucocorticoids and insulin resistance: old hormones, new targets. Clin. Sci. (Lond.) 96, 513–523 (1999).

    CAS  Google Scholar 

  31. Dinneen, S., Alzaid, A., Miles, J. & Rizza, R. Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J. Clin. Invest. 92, 2283–2290 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Yuen, K. C., McDaniel, P. A. & Riddle, M. C. Twenty-four-hour profiles of plasma glucose, insulin, C-peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short-term, medium-dose prednisone (20 mg/day) treatment: evidence for differing effects on insulin secretion and action. Clin. Endocrinol. (Oxf.) 77, 224–232 (2012).

    CAS  Google Scholar 

  33. Phillips, D. I. et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J. Clin. Endocrinol. Metab. 83, 757–760 (1998).

    CAS  PubMed  Google Scholar 

  34. Karatsoreos, I. N. et al. Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse. Endocrinology 151, 2117–2127 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chavez, M. et al. Adrenalectomy increases sensitivity to central insulin. Physiol. Behav. 62, 631–634 (1997).

    CAS  PubMed  Google Scholar 

  36. Cannon, W. B. Bodily Changes in Pain, Hunger, Fear, and Rage (Appleton-Century-Crofts, New York, 1929).

    Google Scholar 

  37. Faulenbach, M. et al. Effect of psychological stress on glucose control in patients with type 2 diabetes. Diabet. Med. 29, 128–131 (2012).

    CAS  PubMed  Google Scholar 

  38. Nowotny, B. et al. Effects of acute psychological stress on glucose metabolism and subclinical inflammation in patients with post-traumatic stress disorder. Horm. Metab. Res. 42, 746–753 (2010).

    CAS  PubMed  Google Scholar 

  39. Gonzalez-Bono, E., Rohleder, N., Hellhammer, D. H., Salvador, A. & Kirschbaum, C. Glucose but not protein or fat load amplifies the cortisol response to psychosocial stress. Horm. Behav. 41, 328–333 (2002).

    CAS  PubMed  Google Scholar 

  40. Ismail, K., Winkley, K. & Rabe-Hesketh, S. Systematic review and meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet 363, 1589–1597 (2004).

    PubMed  Google Scholar 

  41. Kubera, B. et al. The brain's supply and demand in obesity. Front. Neuroenergetics 4, 4 (2012).

    PubMed  PubMed Central  Google Scholar 

  42. Spiegel, K., Leproult, R. & Van Cauter, E. Impact of sleep debt on metabolic and endocrine function. Lancet 354, 1435–1439 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Karatsoreos, I. N., Bhagat, S., Bloss, E. B., Morrison, J. H. & McEwen, B. S. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc. Natl Acad. Sci. USA 108, 1657–1662 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Scheffler, I. E. Mitochondria, 2nd edn (John Wiley & Sons, 2008).

    Google Scholar 

  45. Ballinger, S. W. Beyond retrograde and anterograde signalling: mitochondrial–nuclear interactions as a means for evolutionary adaptation and contemporary disease susceptibility. Biochem. Soc. Trans. 41, 111–117 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wallace, D. C. A mitochondrial bioenergetic etiology of disease. J. Clin. Invest. 123, 1405–1412 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Taylor, R. W. & Turnbull, D. M. Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 6, 389–402 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gómez-Durán, A. et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum. Mol. Genet. 19, 3343–3353 (2010).

    PubMed  Google Scholar 

  49. Safdar, A. et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc. Natl Acad. Sci. USA 108, 4135–4140 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hamilton, M. L. et al. Does oxidative damage to DNA increase with age? Proc. Natl Acad. Sci. USA 98, 10469–10474 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Meissner, C., Bruse, P. & Oehmichen, M. Tissue-specific deletion patterns of the mitochondrial genome with advancing age. Exp. Gerontol. 41, 518–524 (2006).

    CAS  PubMed  Google Scholar 

  53. Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145–147 (1972).

    CAS  PubMed  Google Scholar 

  54. Manoli, I. et al. Mitochondria as key components of the stress response. Trends Endocrinol. Metab. 18, 190–198 (2007).

    CAS  PubMed  Google Scholar 

  55. Taivassalo, T. et al. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 126, 413–423 (2003).

    PubMed  Google Scholar 

  56. Jeppesen, T. D., Orngreen, M. C., van Hall, G., Haller, R. G. & Vissing, J. Fat metabolism during exercise in patients with mitochondrial disease. Arch. Neurol. 66, 365–370 (2009).

    PubMed  Google Scholar 

  57. Morava, E. & Kozicz, T. Mitochondria and the economy of stress (mal)adaptation. Neurosci. Biobehav. Rev. 37, 668–680 (2013).

    CAS  PubMed  Google Scholar 

  58. Westermann, B. Mitochondrial fusion and fission in cell life and death. Nat. Rev. Mol. Cell Biol. 11, 872–884 (2010).

    CAS  PubMed  Google Scholar 

  59. Picard, M., Shirihai, O. S., Gentil, B. J. & Burelle, Y. Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R393–R406 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Liesa, M. & Shirihai, O. S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17, 491–506 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Shutt, T. E. & McBride, H. M. Staying cool in difficult times: mitochondrial dynamics, quality control and the stress response. Biochim. Biophys. Acta 1833, 417–424 (2012).

    PubMed  Google Scholar 

  62. Chen, H. et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141, 280–289 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu, T., Robotham, J. L. & Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl Acad. Sci. USA 103, 2653–2658 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Picard, M. & Turnbull, D. M. Linking the metabolic state and mitochondrial DNA in chronic disease, health and aging. Diabetes 62, 672–678 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Psarra, A. M. & Sekeris, C. E. Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions. Biochim. Biophys. Acta 1787, 431–436 (2009).

    CAS  PubMed  Google Scholar 

  66. Psarra, A. M. & Sekeris, C. E. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim. Biophys. Acta 1813, 1814–1821 (2011).

    CAS  PubMed  Google Scholar 

  67. Sapolsky, R. M. The physiological relevance of glucocorticoid endangerment of the hippocampus. Ann. NY Acad. Sci. 746, 294–304 (1994).

    CAS  PubMed  Google Scholar 

  68. Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl Acad. Sci. USA 106, 3543–3548 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Tang, V. M., Young, A. H., Tan, H., Beasley, C. & Wang, J. F. Glucocorticoids increase protein carbonylation and mitochondrial dysfunction. Horm. Metab. Res. 45, 709–715 (2013).

    CAS  PubMed  Google Scholar 

  70. Madrigal, J. L. et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 24, 420–429 (2001).

    CAS  PubMed  Google Scholar 

  71. Gong, Y., Chai, Y., Ding, J. H., Sun, X. L. & Hu, G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci. Lett. 488, 76–80 (2011).

    CAS  PubMed  Google Scholar 

  72. Rezin, G. T. et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem. Int. 53, 395–400 (2008).

    CAS  PubMed  Google Scholar 

  73. Bennett, M. C., Mlady, G. W., Fleshner, M. & Rose, G. M. Synergy between chronic corticosterone and sodium azide treatments in producing a spatial learning deficit and inhibiting cytochrome oxidase activity. Proc. Natl Acad. Sci. USA 93, 1330–1334 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Hernández-Alvarez, M. I. et al. Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. Antioxid. Redox Signal. 19, 366–378 (2013).

    PubMed  PubMed Central  Google Scholar 

  75. Medikayala, S., Piteo, B., Zhao, X. & Edwards, J. G. Chronically elevated glucose compromises myocardial mitochondrial DNA integrity by alteration of mitochondrial topoisomerase function. Am. J. Physiol. Cell Physiol. 300, C338–C348 (2011).

    CAS  PubMed  Google Scholar 

  76. Suzuki, S. et al. Oxidative damage to mitochondrial DNA and its relationship to diabetic complications. Diabetes Res. Clin. Pract. 45, 161–168 (1999).

    CAS  PubMed  Google Scholar 

  77. Picard, M. et al. Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation. Am. J. Respir. Crit. Care Med. 186, 1140–1149 (2012).

    CAS  PubMed  Google Scholar 

  78. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001–5011 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).

    CAS  PubMed  Google Scholar 

  81. Yakes, F. M. & Van Houten, B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl Acad. Sci. USA 94, 514–519 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kolesar, J. E., Wang, C. Y., Taguchi, Y. V., Chou, S. H. & Kaufman, B. A. Two-dimensional intact mitochondrial DNA agarose electrophoresis reveals the structural complexity of the mammalian mitochondrial genome. Nucleic Acids Res. 41, e58 (2013).

    CAS  PubMed  Google Scholar 

  83. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat. Genet. 2, 324–329 (1992).

    CAS  PubMed  Google Scholar 

  84. Pan, H. Z. et al. The oxidative stress status in diabetes mellitus and diabetic nephropathy. Acta Diabetol. 47 (Suppl. 1), 71–76 (2010).

    CAS  PubMed  Google Scholar 

  85. Aschbacher, K. et al. Good stress, bad stress and oxidative stress: insights from anticipatory cortisol reactivity. Psychoneuroendocrinology 38, 1698–1708 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    CAS  PubMed  Google Scholar 

  87. Passos, J. F., Saretzki, G. & von Zglinicki, T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 35, 7505–7513 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Passos, J. F. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5, e110 (2007).

    PubMed  PubMed Central  Google Scholar 

  89. Oexle, K. & Zwirner, A. Advanced telomere shortening in respiratory chain disorders. Hum. Mol. Genet. 6, 905–908 (1997).

    CAS  PubMed  Google Scholar 

  90. Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Malik, A. N. & Czajka, A. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13, 481–492 (2013).

    CAS  PubMed  Google Scholar 

  92. Rasola, A. & Bernardi, P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12, 815–833 (2007).

    CAS  PubMed  Google Scholar 

  93. Owusu-Ansah, E., Yavari, A., Mandal, S. & Banerjee, U. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat. Genet. 40, 356–361 (2008).

    CAS  PubMed  Google Scholar 

  94. Qian, W. et al. Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress. J. Cell Sci. 125, 5745–5757 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Escames, G. et al. Mitochondrial DNA and inflammatory diseases. Hum. Genet. 131, 161–173 (2012).

    CAS  PubMed  Google Scholar 

  96. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I. M. & Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004).

    CAS  PubMed  Google Scholar 

  99. Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Mathew, A. et al. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J. Alzheimers Dis. 30, 617–627 (2012).

    CAS  PubMed  Google Scholar 

  101. Komili, S. & Silver, P. A. Coupling and coordination in gene expression processes: a systems biology view. Nat. Rev. Genet. 9, 38–48 (2008).

    CAS  PubMed  Google Scholar 

  102. Hunter, R. G. et al. Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc. Natl Acad. Sci. USA 109, 17657–17762 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Nasca, C. et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc. Natl Acad. Sci. USA 110, 4804–4809 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Guha, M., Pan, H., Fang, J. K. & Avadhani, N. G. Heterogeneous nuclear ribonucleoprotein A2 is a common transcriptional coactivator in the nuclear transcription response to mitochondrial respiratory stress. Mol. Biol. Cell 20, 4107–4119 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Romanello, V. et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774–1785 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Holley, A. K. & St Clair, D. K. Watching the watcher: regulation of p53 by mitochondria. Future Oncol. 5, 117–130 (2009).

    CAS  PubMed  Google Scholar 

  107. Schroeder, E. A., Raimundo, N. & Shadel, G. S. Epigenetic silencing mediates mitochondria stress-induced longevity. Cell Metab. 17, 954–964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Wallace, D. C. Bioenergetics and the epigenome: interface between the environment and genes in common diseases. Dev. Disabil. Res. Rev. 16, 114–119 (2010).

    PubMed  Google Scholar 

  109. Elstner, M. & Turnbull, D. M. Transcriptome analysis in mitochondrial disorders. Brain Res. Bull. 88, 285–293 (2012).

    CAS  PubMed  Google Scholar 

  110. Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Slavich, G. M. & Cole, S. W. The emerging field of human social genomics. Clin. Psychol. Sci. 1, 331–348 (2013).

    PubMed  PubMed Central  Google Scholar 

  112. Kuo, L. E. et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat. Med. 13, 803–811 (2007).

    CAS  PubMed  Google Scholar 

  113. Epel, E. S. Psychological and metabolic stress: a recipe for accelerated cellular aging? Hormones (Athens) 8, 7–22 (2009).

    Google Scholar 

  114. Andreux, P. A., Houtkooper, R. H. & Auwerx, J. Pharmacological approaches to restore mitochondrial function. Nat. Rev. Drug Discov. 12, 465–483 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Picard, M. et al. Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle. J. Appl. Physiol. 115, 1562–1571 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Colberg, S. R. et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care 33, 2692–2696 (2011).

    Google Scholar 

  117. Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. McManus, M. J., Murphy, M. P. & Franklin, J. L. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 31, 15703–15715 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. McEwen, B. S. & Wingfield, J. C. The concept of allostasis in biology and biomedicine. Horm. Behav. 43, 2–15 (2003).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Martin Picard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.22

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing