Review
Mitochondria as key components of the stress response

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The exquisitely orchestrated adaptive response to stressors that challenge the homeostasis of the cell and organism involves important changes in mitochondrial function. A complex signaling network enables mitochondria to sense internal milieu or environmental changes and to adjust their bioenergetic, thermogenic, oxidative and/or apoptotic responses accordingly, aiming at re-establishment of homeostasis. Mitochondrial dysfunction is increasingly recognized as a key component in both acute and chronic allostatic states, although the extent of its role in the pathogenesis of such conditions remains controversial. Genetic and environmental factors that determine mitochondrial function might contribute to the significant variation of the stress response. Understanding the often reciprocal interplay between stress mediators and mitochondrial function is likely to help identify potential therapeutic targets for many stress and mitochondria-related pathologies.

Introduction

The acute response to stressful stimuli is characterized by release of stress mediators, including corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), glucocorticoids (GCs) and the catecholamines, adrenaline and noradrenaline. In inflammatory stress, proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 1 (IL-1) and IL-6, are also secreted. The synchronized interaction of stress mediators serve to: (i) maintain effective blood supply (and hence oxygenation and nutrition) primarily to the brain, cardiac and skeletal muscle; (ii) increase energy production through recruitment of substrates (i.e. glucose, fatty acids and amino acids) from body fuel storages (i.e. liver, adipose tissue and skeletal muscle) and enhanced hepatic gluconeogenesis; and (iii) optimize ATP availability to vital tissues at the expense of others (i.e. gonads and gastrointestinal tract) [1]. Excessive or chronic physical, as well as emotional, stress can lead to significant dysregulation and/or failure of the adaptive mechanisms and subsequent increased morbidity and mortality (cardiovascular disease, metabolic syndrome, immunosuppression and depression) [2].

Mitochondria play a vital role in cellular homeostasis. They house the oxidative phosphorylation machinery, which enables aerobic ATP generation, and multiple metabolic pathways, such as β-oxidation of fatty acids and the tricarboxylic acid and urea cycles. Indeed, over 90% of cellular energy generation takes place in the mitochondria. In addition, mitochondria have important biosynthetic activities, control intracellular Ca2+ metabolism and signaling, regulate thermogenesis, generate most cellular reactive oxygen species (ROS) and serve as the gatekeeper of the cell for programmed cell death (apoptosis) [3]. Given their crucial role in cell physiology, it is obvious that mitochondria are among the first responders to various stressors challenging homeostasis of the cell and organism.

Thus, mitochondria are primarily responsible for meeting the enormous energy demands of the ‘fight and flight response’ in vital tissues, by oxidizing the large amounts of substrates that are made available by stress-hormone-induced mobilization from energy storages. In addition, mitochondria control the fever response by modulating thermogenesis, balance the host immune response to infection by regulating the fate of the affected cells and adjust the oxidative stress response for cytoprotective, defense or signaling purposes. The role of mitochondrial ROS-induced DNA damage that might lead to genetic instability and, in turn, development of cancer is outside the scope of this review. Despite growing knowledge regarding each of the above processes, how mitochondria fulfill these demands remains poorly understood.

Here we delineate the main pathways regulating mitochondrial adaptation to stress and the different thresholds for mitochondrial stress-tolerance/resilience. We provide clinical examples highlighting the role of mitochondria in acute and chronic physical or psychological stress states and describe current research efforts to optimize mitochondrial function.

Section snippets

Mitochondria and their adaptive response to stress

The mitochondrial response to emerging cellular needs involves a network of nuclear and mitochondrial signaling pathways (Figure 1) aimed at: (i) increasing mitochondrial performance by recruiting a greater number of mitochondria (biogenesis) and/or increasing their volume; (ii) enhancing the expression and activity of oxidative phosphorylation (OXPHOS) subunits; (iii) fine tuning the uncoupling of the respiratory chain, with consequent release of energy in the form of heat; (iv) facilitating

Mitochondrial resilience

Mitochondrial reserve capacity (i.e. the ability of mitochondria to meet the evolving needs of the cell) is hard to quantify, because the phenotypic expression of mitochondrial impairment is affected by several as yet undefined processes [5]. Mitochondrial resilience results from the unique genetic properties of these organelles. Mammalian cells contain 100–1000 mitochondria per cell and each mitochondrion holds about 5–10 mtDNA copies. Study of patients with inherited mitochondrial disorders

Interplay of mitochondria and stress mediators

Most of the primary mediators of the stress response, including hormones (GCs and catecholamines), immune factors (cytokines) and heat-shock proteins, exert numerous effects on mitochondrial biogenesis, metabolism, ROS generation and apoptosis.

Acute stress

Tissue oxygen consumption and total energy expenditure are increased during the initial phase of the acute stress response (Figure 2). Indeed, energy expenditure is initially enhanced by as much as 200%. Despite significant hyperglycemia, the observed decrease in the respiratory quotient (RQ = 0.8, the ratio of carbon dioxide produced to oxygen consumed) suggests that a significant portion of this energy derives from lipid oxidation occurring primarily in the mitochondria.

Although a burst in

Mitochondrial genetic variation and the stress response

Human populations can be divided into several mtDNA haplogroups on the basis of single nucleotide polymorphisms (SNPs) in the mitochondrial genome. Because mtDNA is maternally inherited, mutations have accumulated by a discrete maternal lineage during evolution. The potential importance of mtDNA haplogroups in predisposition to neurodegenerative disorders and human longevity is increasingly recognized 58, 59, 60. Haplogroup H, the most common in European populations, has been associated with

Quest for ways to empower stressed mitochondria

Calorie restriction and regular physical exercise, the cornerstones in the management of the metabolic syndrome, are the best available enhancers of mitochondrial function. A recent randomized clinical trial demonstrated that in humans prolonged calorie restriction, coupled or not with exercise, resulted in decreased baseline energy expenditure, body temperature and oxidative DNA damage [64]. Similar interventions have increased mitochondrial size and content in skeletal muscle and decreased

Conclusion

Inherited and environmental factors that modulate mitochondrial energy reserves emerge as important and, at times, limiting components of the stress response. Mitochondrial haplogroups, genetic variations or acquired functional changes can be protective or maladaptive during stress. ‘Low-power’ or ‘burned-out’ mitochondria are associated with numerous diseases of public health significance, such as sepsis, the metabolic syndrome and type 2 diabetes. Thus, it appears reasonable to envision a

Acknowledgments

This work was supported by the Intramural Research Programs of the National Institute of Child Health and Human Development, the National Center for Complementary and Alternative Medicine, the National Institute of Mental Health and the National Human Genome Research Institute, National Institutes of Health, Bethesda, US, as well as the University of Athens, Greece. Y.A.S. is supported partially by the NIH research contract: NIH-NIDDK-06-925 from the NICHD Intramural Research Programs

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