The mitochondrial genome is of prime importance because it encodes essential genes for energy production by the respiratory chain. The respiratory chain, also known as the electron transport chain, is located in the tight folds of the inner membrane called “cristae” and contains five multiprotein enzyme complexes—I, II, III, IV, and V (Fig. 1, left). Most of the mitochondrial proteins (>1500) are encoded in the nuclear genome, except for the 13 encoded by the mtDNA (Fig. 2). All mtDNA-encoded proteins are subunits of the respiratory chain complexes I, III, IV, and V. Only complex II (succinate dehydrogenase) is fully encoded by the nuclear genome. The respiratory chain complexes are large enzymes composed of multiple proteins that transport energy in the form of electrons derived from ingested food substrates, initially catabolized by the TCA cycle and β-oxidation. The terminal respiratory chain complex IV (cytochrome c oxidase, or COX) combines the transported electrons with breathed oxygen (O2), which acts as ultimate electron acceptor. The energy harnessed from this process thus establishes the life-sustaining mitochondrial electrochemical gradient (ΔΨ), akin to a charged battery. Generating the mitochondrial electrochemical gradient is the ultimate reason why living organisms must eat and breathe. The flow of energy through mitochondria distinguishes the living person from the inert body; it enables mitochondrial functions required for life.
The energy harnessed from electron transport stored across the inner mitochondrial membrane as membrane potential is used to drive multiple distinct functions. One of the first to be discovered was the production of adenosine triphosphate (ATP) (38), which fuels most cellular reactions, including gene expression, chromatin remodeling, ion homeostasis, protein and hormone synthesis, secretion, neurotransmitter release and reuptake, and muscle contraction, to name a few. The metaphor of “mitochondria as powerhouse” has thus dominated the imagination of biologists and the public over the past half-century. The ability of mitochondria to use oxygen at the level of the respiratory chain complexes, referred to as mitochondrial oxidative capacity, thus depends on a functional respiratory chain and intact mtDNA. Mitochondrial respiratory capacity can be measured directly in fresh cells by respirometry (39–41), or indirectly from frozen samples by measuring the enzymatic activity of respiratory chain complexes (42). Mitochondrial ATP synthesis can also be directly measured in fresh cells (43).
Notably, after screening titles and abstracts, 22 articles listing “mitochondrial function” as a main outcome in the abstract did not actually assess functional measures and were therefore excluded. These articles, some of which are discussed hereinafter in the section “Additional Findings In Animal Studies,” assessed protein markers, gene expression, or other molecular markers (e.g., metabolites and apoptotic cell death). After exclusion of ineligible studies, 23 articles were retained and included in this systematic review.
Four main themes emerge from this body of work. First, chronic stress induced through a form of psychosocial stressor decreases mitochondrial energy production capacity and alters mitochondrial morphology. This manifested at multiple levels, in respiratory chain enzymatic activity of various complexes, in the rate or oxygen consumption (i.e., respiration) measured directly from fresh tissues or isolated mitochondria, in mitochondrial membrane potential, or in mitochondrial content (Table 1).
Second, acute and chronic stressors have different and in some cases opposite effects on mitochondrial functions. Acute stress may damage mitochondrial structure within hours and enhance certain aspects of their function. Several studies investigating mitochondrial morphology and ultrastructure by electron microscopy reported acute mitochondrial damage with stress (53,55,57,70,74), whereas other showed increased size of mitochondria with chronic stress (63), possibly reflecting an increase in biogenesis. Although some studies reported gross disruption in mitochondria indicative of dysfunction and pathological swelling, the lack of quantitative analysis of mitochondrial shape and morphology precludes conclusions regarding the effects of stress on mitochondrial shape. Differential effects on mtDNA copy number (mtDNAcn) have also been reported. One study found 50% to 60% decreased mtDNAcn in various brain regions after chronic unpredictable stress (61), whereas another study revealed increased mtDNAcn in peripheral tissues after chronic restraint stress (52). The liver, in particular, showed the highest change after 4 weeks of stress, with a doubling of mtDNAcn (75). The increase in mtDNAcn is in keeping with compensatory up-regulation of biogenesis and greater mtDNA replication in response to energy deficiency when the mtDNA is mutated (76,77). Antioxidant enzymes may also be up-regulated acutely, likely as an adaptive response, but then decrease with chronic restraint stress (78,79). Overall, these data are consistent with an inverted U-shaped relationship linking the duration of psychosocial stress with mitochondrial changes, and mitochondrial allostatic load (MAL) more generally (21).
Third, because parts of the respiratory chain are encoded by mtDNA and other components are not, comparing them allows us to discern functional changes that could arise form mtDNA defects and those arising from other mechanisms, such as changes in biogenesis or regulatory molecular modifications of various proteins. Among the respiratory chain complexes, complex IV (COX), which is encoded by the mtDNA, was the most frequently affected. Studies, mostly conducted with the brain, reported changes in COX activity ranging from 0 to 80% decreased specific COX activity. Unlike other enzymes, no study found increase in COX activity from stress. However, one study found selective decrease in complex I and complex II (succinate dehydrogenase), but not in COX (62).
Fourth, certain factors can influence mitochondrial vulnerability to stress. One study did not find significant alterations of mitochondria function in normal mice, but observed a significant decrease in COX activity in transgenic mice (lacking the Malpar1 gene) (54). Such observation suggests that genetic factors can sensitize or confer a predisposition of mitochondria to the effects of psychological stress. Although not the direct focus of this review, several studies also included an intervention arm where animals either exercised or received specific small-molecule compounds acutely or chronically before stress exposure. As indicated in Table 1 (see results marked with “[ ]”), certain compounds including antioxidants conferred protection against stress-induced mitochondrial dysfunction (64,65,67,68), indicating the existence of stress-sensitizing and stress-buffering factors (i.e., moderators) for the effects of induced stress on mitochondria.
This section discusses some studies that did not meet the criteria for inclusion in the present systematic review of the literature because they did not directly measure mitochondrial function, but nevertheless provided strong complimentary indirect evidence that stress alters some aspect of mitochondrial energetics. For example, some studies described herein evaluated specific molecular components of mitochondria (e.g., proteins inside mitochondria), which, although they do not represent function, may reflect some form of molecular recalibration and could constitute the molecular basis for functional defects observed in functional studies. In this section we discuss examples of these complimentary outcomes, which when assessed in parallel with functional outcomes will reinforce the interpretation of future studies.
Some studies analyzed stress biomarkers in rats exposed to chronic mild unpredictable stress using metabolomics. Metabolomics allows for the unbiased detection of hundreds to thousands of metabolites, many of which are directly or indirectly derived from mitochondrial metabolism (80). One study in particular showed circulating metabolic profiles in response to induced stress that are suggestive of altered energy metabolism implicating mitochondrial respiratory chain dysfunction (81). Mice with different anxious-like behavior (e.g., avoidance of open spaces) also have different metabolomic signatures in the brain and blood (82). Interestingly, parallel work in humans has also related various emotional states (e.g., depressive symptoms) to certain metabolomic profiles, such as amino acids, using cross-sectional research designs (20,83).
Other studies have performed detailed analyses of the ensemble of proteins contained in mitochondria using proteomics, finding widespread changes in the protein composition of brain mitochondria under stress (84). The mitochondrial proteome also differs between mice with low- versus high-anxiety–like behaviors (85), suggesting that different mitochondrial phenotypes in the brain may be at the origin of anxious traits and social behavior (86) and influence physiological stress responses (87), as discussed previously.
One study found higher mtDNAcn in whole blood from American individuals who had endured either parental loss or childhood maltreatment (adverse childhood experiences, or ACEs) and with psychopathology including major depression, depressive disorders, anxiety disorders, and substance abuse disorders compared with controls without ACE (94). Another study measured whole-blood mtDNA in Chinese women with clinical levels of depressive symptoms, and also found higher mtDNAcn (52) and higher levels of mtDNA mutations (i.e., heteroplasmy) compared with women without depression (75). However, these studies are confounded by the use of whole blood (95,96) (see discussion of limitations hereinafter) and the cross-sectional study design, which cannot tease apart directionality or causality. Whether psychological symptoms (e.g., anhedonia and sadness in major depression) cause changes in mtDNA, or whether changes in mtDNA reflect an underlying pathophysiological state that contributes to psychological symptoms (i.e., reverse causation), remains to be determined.
Another study measured mitochondrial respiration and cellular mitochondrial content in frozen leukocytes of women retrospectively reporting ACEs (91). Using the Childhood Trauma Questionnaire, women were categorized as having “none,” “low/moderate,” or “severe” childhood maltreatment load based on the sum of their ACE frequency. This study found that compared with those who reported no maltreatment load, women with a severe load had blood leukocytes consuming more oxygen under basal (unstimulated) conditions. This result could reflect the combined product of energy demand by the cell and endogenous mitochondrial function, suggesting that early life trauma may reprogram cellular energetics (91). However, it does not specifically reflect mitochondrial dysfunction. Mitochondrial content, assed by citrate synthase (CS) activity, was also similar between individuals with varying levels of childhood trauma and controls. Notably, this research revealed that certain mitochondrial respiratory parameters were correlated with systemic inflammatory markers. Thus, these findings hint at two possibilities: either that stress-induced inflammation influences cell energetics, or that experiencing such psychosocial stressors (and potentially the emotional responses associated with these experiences) causes alterations in cellular or mitochondrial energetics, which in turn induce inflammation. The second possibility is consistent with in vitro work and mitochondrial stress transduction leading to biological embedding of life exposures (21), but further work is needed to establish the directionality of these effects.
One study evaluated the levels of circulating cell-free mtDNA (ccf-mtDNA) in plasma from individuals after nonviolent suicide attempt, an acute stressful event presumably preceded by psychological distress, compared with individuals who did not engage in suicidal behaviors (92). Suicide attempters had strikingly elevated (Cohen d = 2.6) level of ccf-mtDNA compared with controls, possibly reflecting MAL. Because ccf-mtDNA lies outside the cells, circulating in the liquid fraction of blood, it does not contribute to tissue energy production capacity and therefore does not represent mitochondrial function. Current evidence suggests that ccf-mtDNA is a general sign of physiological stress particularly induced by injury and associated with inflammation (21,97). It will therefore be interesting to understand the link between psychological stress, the neuroendocrine and cellular factors that lead to mtDNA release, and both their immediate and long-term physiological effects.
Another study targeted caregiver women who care for a child with autism spectrum disorder, which is a psychopathology that fosters elevated levels of psychological distress in the caregivers given its detrimental impact in various life domains of the child (e.g., persistent deficits in social communication, stereotyped or repetitive behaviors and interests). The authors measured respiratory chain maximal enzymatic activities, mitochondrial content, respiratory chain protein abundance, and mtDNAcn in isolated mixed blood cells (93). Although mitochondrial content was unaltered, mitochondrial respiratory chain activity per mitochondrion–indexed as mitochondrial health–was significantly lower in caregivers compared with controls, with the largest group difference effect size being for COX (which is mtDNA-encoded). This result is similar to findings in animal models which, collectively, implicate mtDNA-encoded components that may decrease the overall energy production capacity of mitochondria in blood cells exposed to chronic stressors. Of relevance to the psycho-somatic model, this study found that morning and evening mood on days preceding blood draw accounted for 12% to 15% of the variance in the mitochondrial health index (MHI) on subsequent days, but not the reverse, suggesting that mitochondria respond to proximal emotional states. Accordingly, lower positive mood was a significant mediator of the effect between the chronic life stressor (i.e., caregiving of a child with autism spectrum disorder versus controls) and poorer mitochondrial health (93), potentially indicating a directional effect of acute psychological states on mitochondrial function.
Overall, there are very few studies in human subjects and most did not directly assess mitochondrial function. Nevertheless, the preliminary data available thus far support a potential association of psychosocial stressors and psychological distress with some aspects of mitochondrial function, but limitations in design and methodology encourage caution in interpreting these results.
Evidence from metabolomic, proteomic, and transcriptomic studies also suggest additional layers of regulation by which stressful experiences may alter mitochondrial components among rodents. Although these metabolites, protein composition, and gene expression outcomes do not reflect the functionality of mitochondria, when assessed in parallel with functional outcomes, they will help explain and refine our understanding of the mechanisms by which stress influences mitochondrial function and health. In addition, whereas functional changes should be regarded as primary indicators of MAL (21), stress-induced molecular changes within mitochondria may also reflect compensatory mechanisms or recalibrations that contribute to long-term changes in mitochondrial function and to the accumulation of MAL.
Albeit informative, the reviewed animal studies include some major limitations. a) The lack of direct measurement of mitochondrial content to normalize activity metrics makes it impossible to distinguish between overall decrease in mitochondrial content and decreased function or “quality” of individual organelles. This would be resolved by measuring in parallel both markers of mitochondrial content and function in future work. b) Another limitation is the improper methodology to measure mitochondrial membrane potential, which could be improved by the use of ratiometric dyes, and also controlling for mitochondrial content. c) Within each study, analyses were conducted mostly in only one tissue, not enabling to determine the general versus tissue-specific effects of induced stress. d) The studies using prolonged stressors (e.g., restraint for >8 hours) do not always specify whether such duration prevented normal feeding/drinking, which could either counteract or further exaggerate some effects of stress on mitochondrial functions. e) Restraint stress paradigms commonly used could be construed as a “physical” stressor, and consequently, the mitochondrial changes reported may reflect physical rather than psychological stress. It is also apparent that stress induction paradigms and methodologies are not uniform across laboratories, which could contribute to discrepancies in the effects of stress on mitochondrial outcomes outlined in this systematic review. This is also true of assays used to characterize mitochondrial functions, because specific methods favored and available vary from one laboratory to another. Only few studies, apart from those assessing respiratory chain enzymatic activity in brain showing consistent overall decrease maximal enzymatic activity, have been replicated and have provided a satisfactory level of confirmation.
Perhaps the most notable and ubiquitous limitation of existing studies reviewed here is the exclusive use of male animals. This is largely explained by the common assumption in preclinical research that compared with male rodents without an estrous cycle, animal-to-animal variability is greater, and the data therefore are more “messy,” in females. However, this assumption is largely incorrect in regard to behavioral, metabolic, hormonal, and morphological traits (98). However, this still pervasive bias remains a significant obstacle to generalizability and to our ability to translate these data into human research (99). Given substantial sex differences in mitochondrial biology and their responses to perturbations (100) stress-related mitochondrial studies will benefit from equal inclusion of both sexes.
Existing human studies underscore five main limitations and point the way toward more robust research. The first limitation is the use of single molecular mitochondrial markers, which do not directly reflect mitochondrial function. Certain mitochondrial outcomes such as mtDNAcn, do not directly reflect mitochondrial function. In the absence of functional measures, the physiological meaning of increases and decreases of mtDNAcn is unclear and impossible to conclusively interpret. This is especially true in cases where mtDNAcn is measured from whole blood, which is composed of several different immune and nonimmune cell types with different mtDNA levels. Moving forward, dynamic measures of mitochondrial function could be assessed in parallel with molecular markers of mitochondrial content. Metrics of function and content could also be combined into indices of MHI that may be more sensitive and precise than individual markers alone (93). Improving the sensitivity of mitochondrial outcomes will provide more robust evidence into the link of psychosocial stressors and emotional states with mitochondria.
The second and related limitation is the use of mixed blood cell populations. Blood immune cell composition changes dynamically with various stress indicators (95,96) and undergo substantial circadian (i.e., across the day) oscillations (101). This is relevant because each immune cell type contains different amount of mitochondria that exhibit qualitatively different functions (102). Thus, the relative abundance of different leukocytes subpopulations could substantially alter mitochondrial measures without any real change in mitochondrial function in any cell type. For example, a small change in the proportion of platelets, an enucleated cell type that contributes to coagulation, artificially alters apparent mtDNAcn when measured in whole blood or in peripheral blood mononuclear cells contaminated with platelets (103,104). Future studies would be strengthened by the isolation of specific leukocyte populations. When it is not possible to sort different cell types, avoiding platelet contamination in peripheral blood mononuclear cells (PBMCs), with appropriate platelet depletion steps, would improve the interpretability of mitochondrial function data.
A third limitation of human studies is the exclusive use of blood-derived immune cells. Mitochondria are present in all tissue types, and stress-induced mitochondrial dysfunction could be tissue-specific. Some psychosocial stressors and emotional states may preferentially affect brain mitochondria (contributing to neurological disorders and cognitive decline), whereas others may affect liver and heart mitochondria (contributing to metabolic disorders). Other than blood, biopsies of other tissues are amenable to mitochondrial assessments, including buccal and urinary epithelial cells, as well as fat and skeletal muscle, among others. Certain immune cell subtypes (e.g., monocytes versus granulocytes and memory versus effector lymphocytes) may also be differentially affected. Although studies in leukocytes can be informative of mitochondrial health in immune cells themselves, studies incorporating measures across different accessible tissues and cell types will be insightful to understand the broader relevance—both diagnostic and prognostic—of mitochondrial function and mtDNAcn.
A fourth limitation relates to the retrospective and cross-sectional design of human studies. In comparison to experimental studies such as those reviewed previously where stress exposure is manipulated by experimenters, all human studies so far have compared groups that differ in the experience of psychosocial stressors (e.g., exposure or not to early life stress) or in the levels of psychological distress (e.g., presence versus absence of psychiatric disorders). Such designs limit conclusions about causality and cannot rule out the contribution of potential covariates (e.g., exercise, sleep, and nutrition). Longitudinal and prospective study designs with comprehensive assessment of potential covariates such as physical activity, as well as studies monitoring emotional stress with repeated measures of mitochondrial function, are needed to establish the directionality of effects linking psychosocial stressors, the resulting emotional responses, and mitochondrial functions in humans.
Finally, the fifth limitation noted is the unequal representation of sex in current studies. Contrary to animal studies that exclusively included males, human studies have predominantly included women (see Table 2). Because of known sexual dimorphism in mitochondrial functions (101), research with balanced sex (and gender) composition will be needed to achieve a complete picture of mitochondrial recalibrations in men and women. In addition, so far, human studies have only concentrated on young adults or middle-aged individuals. Considering both sex and age in future research will enable building a more accurate and generalizable understanding of the role of mitochondrial dysfunction in stress pathophysiology in the population and across the life-span. We next discuss processes within mitochondria that may contribute to resilience and possibly explain the effects of stress-buffering interventions on mitochondrial health and downstream stress biomarkers.
As discussed previously, mitochondrial oxidative stress is an indicator of MAL that contributes to stress pathophysiology (reviewed in Ref. (105)). The corollary is that mitochondrial antioxidant capacity should buffer against the effects of chronic stress. Although the major source of ROS and oxidative stress within cells is generally mitochondria (35), oxidative damage from stress could be of mitochondrial or of other origin. In line with the idea that mitochondrial oxidative stress contributes to cellular dysregulation, enhancing mitochondrial antioxidant capacity by experimentally overexpressing antioxidant enzymes in mouse mitochondria was previously shown to increase resilience to metabolic stress (106,107) and even increase life-span in mice (108). Likewise, oral administration of a mitochondria-targeted antioxidant decreased anxiety-like behavior in inbred mice selected for high-anxious traits (109). A similar effect was observed for depressive-like behaviors with the administration of the mitochondrial metabolite acetyl-L-carnitine (110,111). Similarly, chronic mild stress induces depression-like behavior in normal mice, which is counteracted by the induction of mitochondrial biogenesis in skeletal muscle via the overexpression of peroxisome proliferator–activated receptor-γ co-activator 1α (PGC-1α) (112). Similarly, low sociability usually associated with peripubertal stress is reverted by brain injection of resveratrol, a compound that stimulates mitochondrial biogenesis (113). This body of evidence indirectly supports a role of mitochondrial oxidative stress and mitochondrial function in stress pathophysiology.
However, it remains to be established whether the pathophysiology associated with chronic stress can be prevented or mitigated by mitochondria-targeted interventions, and whether this could be applied in humans. Certain behaviors like physical activity and exercise may have biological stress–buffering effects in humans (114,115). Interestingly, exercise increases several markers of mitochondrial content and function both in humans and in rodents (61,116,117). Furthermore, in one study where stressed sedentary animals experienced a decrease in respiratory chain enzymatic activities, animals trained with treadmill running showed the expected increase in mitochondrial content and function, and in parallel exhibited partial to complete protection against the stress-induced decreases in mitochondrial function and mtDNAcn (61). In humans, acute exercise before a series of mental arithmetic challenges along with social evaluative threat has also been shown to modulate hypothalamic-pituitary-adrenal (HPA) axis reactivity as well as hippocampal and prefrontal cortex activation (118). Because exercise acutely changes mitochondrial function and chronically increases in mitochondrial content and function in various organs, it is possible that the stress-buffering effects of exercise in humans could be mediated by changes of mitochondrial function. This possibility remains to be empirically evaluated.
Building from established models where psychosomatic processes are known to operate, incorporating mitochondrial measures in study designs should accelerate the progression of our understanding around the interaction of mitochondria with the broad-acting brain-immune-endocrine processes that affect health outcomes. This joining of disciplines under a shared “psycho-mito-somatic” framework, as discussed in the joint article in this issue of Psychosomatic Medicine (21), should simultaneously promote a more holistic understanding of the processes that precipitate dysregulation and disease within the organism, and of the mechanisms that enable healthy individuals to successfully adapt to life challenges.
The authors are grateful to Claudia Trudel-Fitzgerald for valuable edits to this article and to Robert-Paul Juster for retrieving articles for the systematic review.
Source of Funding and Conflicts of Interest: Support for this work was provided by the Wharton Fund, National Institutes of Health grants R35GM119793 and R21MH113011 (M.P.), and Hope for Depression Research Foundation (B.S.M.). The authors have no conflict of interest to report.
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