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Background: The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psychological states. Methods: A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress response, and its implementation in behavioral and psychosomatic medicine. Results: Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain, the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates the rate of cellular aging. Conclusions: This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the resulting emotional responses-both adverse and positive-into clinically meaningful biological and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities to investigate how psychosocial factors influence human health and well-being across the life-span.
Possible inverted U-shaped mitochondrial responses to chronic stress. A, Biphasic mitochondrial stress responses as a form of mitohormesis (54), as induced by glucocorticoids (e.g., Ref. (14)). The transition from adaptive to maladaptive is marked by the inversion of the curve at the top. Each line depicts a cellular or physiological system with a different degree of resilience, as indicated by the duration for which it can sustain an adaptive response to the stressor before undergoing a decline in mitochondrial health below baseline. B, The adaptive capacity of mitochondria can vary, as indicated by the degree to which they can generate an adaptive increase in function during stress, depicted hereby the height of curves. C, Certain stressors, particularly during sensitive developmental windows, can also have longterm programming effects that establish lasting set points (detrimental or protective) for mitochondrial health. For example, antiretroviral pharmacotherapy for HIV-AIDS may lead to the permanent accumulation of mtDNA defects that undermine respiratory chain function and decrease baseline function (55). Subsequent exposures (arrows) may have additive effects and further decrease function (below baseline), as a form of detrimental embedding. On the other hand, positive behavioral exposures such as exercise training can increase basal mitochondrial function (above baseline), as a form or protective embedding. mtDNA = mitochondrial DNA. Color image is available only in online version (
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Psychological Stress and Mitochondria:
A Conceptual Framework
Martin Picard, PhD, and Bruce S. McEwen, PhD
Background: The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress
response biomarkers. Mitochondria, a subcellular organellewith its own genome, produce the energy required for life and generate signals
that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral
factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psycho-
logical states.
Methods: A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress
response, and its implementation in behavioral and psychosomatic medicine.
Results: Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional
recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain,
the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic
basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and
other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates
the rate of cellular aging.
Conclusions: This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing
psychosocial experiences and the resulting emotional responsesboth adverse and positiveinto clinically meaningful biological
and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects
of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities
to investigate how psychosocial factors influence human health and well-being across the life-span.
Key words: psychosomatic medicine, mitochondrion, psychoneuroendocrinology, mind-body, mitochondrial allostatic load.
Foundational work in psychosomatic medicine first documented
the main effects of psychological states such as fear and anger,
and social stressors including social isolation, on health outcomes
and mortality. The field then rapidly advanced by exploring the
underlying behavioral, biological, and physiological pathways in
search of modifiable mechanisms that would explain these associ-
ations and for which interventions could be targeted. Early on, this
effort was guided by Engel's (1) biopsychosocial model, the psy-
choneuroimmunology (PNI) framework (2), and more recently
by the allostatic load model of chronic stress (3). These and asso-
ciated models have enabled significant strides toward identifying
mechanisms by which psycheand somaare functionally
linked, as originally envisioned by the founders of Psychosomatic
Medicine (4). Investigators have since focused on biological
mediators of the stress-disease cascade including specific molecu-
lar changes, hormones, metabolites, and cytokines that reflect
cellular activity. Identifying hardwired mechanisms linking
psychosomatic processes to elements of the biopsychosocial
model and to the current biomedical framework has thus contrib-
uted to a deeper understanding of interrelated psychological and
somatic processes.
AIDS = acquired immunodeficiency syndrome, ATP = adenosine
triphosphate, ccf-mtDNA = circulating cell-free mitochondrial DNA,
GR = glucocorticoid receptor, HIV = human immunodefi-
ciency , HPA = hypothalamic-pituitary-adrenal, IL-6 =interleukin
6, LAC = acetyl-L-carnitine, MAL = mitochondrial allostatic load,
mtDNA = mitochondrial DNA, mtDNA deletion =deletionofan
mtDNA segment, PNI = psychoneuroimmunology, ROS = reactive
oxygen species, SAM = sympathetic-adrenal-medullary, TNF-α=
tumor necrosis factor α
From the Department of Psychiatry, Division of Behavioral Medicine (Picard), Department of Neurology, The H. Houston Merritt Center, Columbia
Translational Neuroscience Initiative (Picard), and Columbia Aging Center (Picard), Columbia University; and Laboratory for Neuroendocrinology
(McEwen), The Rockefeller University, New York, New York.
Address correspondence to Martin Picard, PhD, Department of Psychiatry, Division of Behavioral Medicine, Columbia University Medical Center, 622
West 168th St, PH 1540, New York, NY 10032. E-mail:
Received for publication February 4, 2017; revision received September 18, 2017.
DOI: 10.1097/PSY.0000000000000544
Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society. This is an open-access
article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permis-
sible to download and share the workprovided it is properlycited. The work cannot be changedin any way or used commercially without permission from
the journal.
Psychosomatic Medicine, V 80 126-140 126 February/March 2018
Work in psychosomatic medicine is driven by the collective
vision to integrate biological, psychological and social factors
in medicine.Past success indicates that this endeavor is facilitated
by the identification of biological intersection pointswhere
psychosocial and biological factors meet,interact, and trigger
measurable cellular and health effects (5). The immune system
represents such an intersection point (6). Immune cells respond
to neuroendocrine substrates of psychological states and interact
with biological entities such as the human immunodeficiency virus
(HIV), which in turn alter immune responses impacting wound
healing, acquired immunodeficiency syndrome (AIDS) progression,
and clinical outcomes (7). The brain is also a notable example,
responding acutely and chronically to emotional and environmen-
tal perturbations, interacting broadly with other neuroendocrine
and immune systems, and undergoing changes in both structure
and function that impact health throughout human development
(8,9). The successes of PNI and brain remodeling research highlight
the notion that identifying biological intersection points is a
productive endeavor for psychosomatic medicine research.
This article examines the mitochondrion, a multifunctional life-
sustaining organelle, as a potential biological intersection point in
psychosomatic medicine. The first section begins with an intro-
duction about the origin and functions of mitochondria for the non-
expert. A summary of the evidence that mitochondrial function and
dysfunction contribute to systemic physiological (dys)regulation is
then presented. We discuss progress in mitochondrial medicine
and psychosomatic research demonstrating that the systemic path-
ophysiological states triggered by either mitochondrial defects or
chronic stress exposure overlap, implicating similar cellular mech-
anisms. This overlap primarily involves the brain, neuroendocrine
processes,and the immune system, suggesting that disease-causing
psychosomatic processes could in part act via mitochondrial dys-
function. A systematic review of experimental evidence from an-
imal studies and preliminary work in humans presented in the
associated article (10) indicates that chronic and acute stress ex-
posures alter specific aspects of mitochondrial structure and
function. This may result in the accumulation of adaptive and
maladaptive recalibrations in mitochondria in response to stress,
here described as mitochondrial allostatic load (MAL). Finally,
the last section discusses molecular and physiological processes
that link MAL to accelerated cell aging and increased disease
risk. This article concludes with highlighting important knowl-
edge gaps and opportunities for psychosomatic mitochondrial re-
search to advance our understanding of the stress-disease cascade.
The mitochondrion (plural, mitochondria) is an intracellular organ-
elle that evolved from an endosymbiotic relationship. Approxi-
mately 2 billion years ago, an oxygen-consuming bacterium (to
become the mitochondrion) was engulfed by a host cell that lacked
mitochondria (to become today's mammalian cell) (11). Complex
multicellular lifehumans includedemerged from this endosym-
biosis (12). As a result, mitochondria now sustain human life via en-
ergy production and intracellular signaling. Each cell of the body,
with the exception of red blood cells that transport oxygen, contains
hundreds to thousands of mitochondria (Fig. 1A). They are the only
organelles to house their own genome. The mitochondrial genome,
also known as mitochondrial DNA (mtDNA), contains genes that
are critical to the flow of energy through the electron transport
chain. The electron transport chain, or respiratory chain, enables
mitochondria to use oxygen and food substrates to generate a
charge called the mitochondrial membrane potential (ΔΨm). In the
same way that batteries store electrical charges that can subsequently
be used to power various devices, organisms essentially breathe
and eat to charge their mitochondria. This charge is then used to
produce energy in the form of adenosine triphosphate (ATP) to
power neural activity, the heartbeat, muscle contraction, digestion,
and every other cellular activities that occur under resting conditions,
and during stress. Cells that need more energy typically have
more mitochondria (Fig. 1B). However, mitochondria are more
than the powerhouse. They sense, integrate, and signal information
about their environment.
Mitochondria sense stress mediators. Of relevance for psycho-
somatic research, mitochondria evolved to be sensitive to a wide
variety of environmental, metabolic, and neuroendocrine stressors
and stress mediators, including glucocorticoids (13,14), estrogen
(15,16), angiotensin (17), and cannabinoids (18). Metabolic stress,
including high blood glucose and lipids, also influences dynamic
processes of fusion and fission that remodel mitochondrial shape
within the cytoplasm (Fig. 1C) (19,20).
Mitochondria dynamically interact with each other and re-
spond to stressors. There are specialized intermitochondrial junc-
tions that resemble synapses in the brain (21) and thin tubular
connections (22) through which mitochondria exchange infor-
mation among each other. In response to environmental signals,
mitochondria also undergo dynamic morphological and func-
tional changes. Chronically, these alterations of mitochondrial
structure and function can lead to functional recalibrations (23)
and to the accumulation of mtDNA damage (24). The accumula-
tion of mtDNA defects impairs bioenergetics, is generally long
lasting, and may be amplified over time (25).
Mitochondria generate signals of adaptation. Within the cell,
mitochondria are near the cell nucleus (see Fig. 1C). Changes in
mitochondrial functions modify cellular bioenergetics (23), lead-
ing to the production of biochemical signals to which the cell
and its plastic (epi)genome have evolved molecular sensitivity
(2629). Mitochondria speak the language of the epigenome and
multiple mechanisms link their functions to fundamental aspects
of cellular health. In fact, most of the human genome is under
mitochondrial regulation (30). Systemically, mitochondria in
lower organisms produce signalsmitokineswith broad actions
throughout the organism (31,32). It is also interesting to note in
the context of stress regulation that all steroid hormones, including
glucocorticoids and sex hormones, are synthesized in a process
that is regulated by and occurs in mitochondria (33,34), further
linking mitochondrial biology to stress signaling.
As discussed in the subsequent sections, the evolutionary-
acquired critical role of mitochondria in complex life and stress
responses helps to rationalize why mitochondriaa subcellular
organelleregulate whole-body physiological functions includ-
ing the nervous, endocrine, and immune systems. This also helps
to explain how genetic mitochondrial defects may influence com-
plex whole-body physiological processes such as the stress re-
sponse (35), the aging process, and multiple complex diseases
that challenge modern medicine (36).
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Psychosomatic Medicine, V 80 126-140 127 February/March 2018
Across all areas of medicine, mitochondrial research is on the rise.
The number of medical publications related to mitochondria has
increased at a faster pace than those for other organelles, including
the nucleus and genomic studies, which have steadily declined in
the postgenomic era(37). The rising interest for mitochondria
in medical research likely stems, on one hand, from more accessible
tools to grasp the complexity of mitochondria functions (38) and, on
the other hand, from a growing number of medical conditions now
recognized to be caused or promoted by mitochondrial defects (36).
The discovery in the 1980s by Wallace and colleagues (39) that
the mtDNA is maternally inherited that defects on the mtDNA (i.e.,
point mutations and deletions of mtDNA fragments) caused serious
diseases (40) was a breakthrough for molecular medicine. It is now
established that more than 200 inherited genetic defects cause a
broad range of neurological, endocrine, immune, and cardiovascular
FIGURE 1. Mitochondrial content and function in humans. A, Hundreds of mitochondria are present within various cells and organs across
the body. B, Mitochondrial content (i.e., the total amount of mitochondria per cell) varies according to energy demand in different organs,
where they perform multiple functions ranging from energy transformation, signaling, and hormone biosynthesis. C, General schematic
of a cell, its cytoplasm (green), nucleus (blue), and mitochondria (brown). Mitochondria are dynamic and undergo changes in shape
through fusion and fission within minutes in response to external biochemical and energetic signals. Because mitochondria dynamically
fuse with each other (fusion) and fragment (fission), they cannot be counted. RBCs = red blood cells; PBMCs = peripheral blood
mononuclear cells; ATP = adenosine triphosphate; ROS = reactive oxygen species. Color image is available only in online version
Psychosomatic Medicine, V 80 126-140 128 February/March 2018
symptoms (41,42). In milder forms, mitochondrial disorders cause met-
abolic disease (e.g., diabetes) and progressive age-related multisystemic
disorders associated with morbidity and increased mortality, whereas
in most severe cases, they cause death in the first years of life (43).
Like psychosocial stress and trauma (4446), mitochondrial defects
influence various physiological functions and physical conditions
at multiple developmental stages across the life-span.
With the historical role attributed to mitochondria as the cell's
powerhouse, it was naturally believed that mitochondrial disorders
were caused by energy deficiency. However, the recent recognition
of nonenergetic roles of mitochondrial sensing, communication, and
signaling has revealed a new paradigm where multiple mechanisms
cooperate to translate abnormal mitochondrial function into path-
ophysiology. Of particular interest for psychosomatic medicine,
mitochondrial dysfunctions affects most deeply the nervous, endo-
crine, and immune systems, which are understood to play central
roles in allostasis and stress pathophysiology (47). The subsequent
sections reviews evidence that mitochondria regulate key stress-
related physiological systems, which contribute to systemic allostatic
load as originally defined. Furthermore, we discuss the concept of
MAL, which also develops intracellularly at the level of mitochondria
and may contribute to systemic allostatic load (Fig. 2).
Allostasis is the active process of the body adapting to stress via
mediators such as cortisol and the autonomic, metabolic, and im-
mune systems that act together to maintain homeostasis (49).
Allostatic load refers to the cumulative effect of multiple stressors
as well as the dysregulation of the nonlinear network of allostasis
(e.g., too much or too little cortisol, or adrenalin, or prolonged in-
flammatory response to a challenge). Allostatic overload refers to
the cumulative pathophysiological changes that can result from
this dysregulation, both at the cellular and organ levels. The con-
cepts of allostasis and allostatic load and overload emphasize
that the same systems that help the body and brain adapt to ex-
periences also contribute to pathophysiology when the same
mediators are overused or dysregulated among themselves
(50). Moreover, health-promoting and health-damaging behav-
iors that often accompany stressful experiences and, more gen-
erally, living in stressful social and physical environments all
contribute to allostatic load and overload (49).
Mitochondria contribute to allostasis and allostatic load of
the whole individual while having their own forms of allostasis
and allostatic load within cells. The sequence of events, starting
FIGURE 2. Model of MAL as a source of systemic allostatic load. Mitochondrial allostasis is the active process of responding to
challenges including the demand for ATP and other biomolecules to maintain cell function and survival, as well as providing
biochemical signals (e.g., limited amount of ROS). MAL is defined as the dysregulation mitochondrial functions resulting from the
structural and functional changes that mitochondria undergo in response to stressors. Challenges that overwhelm the capacity to
respond and produce an imbalance contribute, over time, to impaired cell function, senescence, and even cell death. Clinical cases
of inherited mitochondrial disorders demonstrate the direct influence of mitochondrial dysfunction on multiple organ systems.
Because mitochondria are intrinsic partners and participants in systemic allostasis (48), MAL is a nested construct that contributes
to systemic allostatic load and overload. MAL = mitochondrial allostatic load; ATP = adenosine triphosphate; ROS = reactive oxygen
species. Color image is available only in online version (
Stress and Mitochondria
Psychosomatic Medicine, V 80 126-140 129 February/March 2018
FIGURE 3. Mitochondrial stress transduction. (Left) Conceptual model of mitochondrial stress pathophysiology outlining the effects of
psychosocial factors on health and disease risk via mitochondria. Mitochondria interact bidirectionally with stress mediators of allostasis,
contributing to physiological stress responses and multisystemic recalibrations from psychosocial factors and stressors. Chronic activation
of these systems leads to MAL, which is transduced through molecular signals into systemic pathophysiology, AL, and molecular changes
within cells. Relationships between psychosocial factors (green boxes, top of figure) and pathophysiological measures (blue boxes, near
bottom of figure) can be modeled statistically as a direct effect with mitochondria as mediator/moderator. (Right) Schematic representation
of mitochondrial sensing, integration, and signaling of life exposures, including psychosocial stressors and emotional (negative and positive)
states. Three main testable corollary hypotheses arise from this model: a) exposure to psychosocial factors and stressors induce MAL;
b) MAL and primary mitochondrial defects cause systemic dysregulation and adverse health outcomes; and c) the end effect and biological
embedding of the same exposure will differ based on the mitochondrial health of the system/individual. Bidirectional relationships exist
between some biobehavioral and psychosocial factors, but are not depicted here for parsimony. MAL = mitochondrial allostatic load;
AL = allostatic load; ACE = adverse childhood experience; ccf-mtDNA = circulating, cell-free mitochondrial DNA; HPA = hypothalamic-
pituitary-adrenal; SAM = sympathetic-adrenal-medullary; HPG = hypothalamic-pituitary-gonadal; HRV = heart rate variability; ROS =
reactive oxygen species; mtDNA = mitochondrial DNA; IL-6 = interleukin 6; TNF-α= tumor necrosis factor α; IL-18 = interleukin 18.
Color image is available only in online version (
TABLE 1. Potential Markers of MAL
Mitochondrial Features Examples Physiological Effects
Mitochondrial content Decreased or increased mitochondrial
number, mitochondrial size
Energy production capacity,
metabolic regulation
Molecular damage Oxidized mtDNA, proteins, and lipids Multiple effects
Molecular composition Lipid and protein composition Multiple effects
Dynamics, morphology, and ultrastructure Fragmented, elongated, or donut
morphology; reduced number or
abnormal cristae
Energy production capacity,
oxidative stress, apoptosis,
systemic metabolic regulation
Genetic (mtDNA) mtDNA copy number per cell, mtDNA
mutations and deletions
Energy production capacity, aging,
systemic metabolic regulation
Respiration and OXPHOS RC enzymatic activity, oxygen
consumption rate, ATP synthesis
Energy production capacity, multiple
functions (gene expression,
endocrine, metabolic)
Other mitochondrial functions ROS production, calcium uptake and
release, decreased membrane
potential, steroid hormone biosynthesis
Multiple functions (gene expression,
endocrine, metabolic, tissue repair)
Mitokine production and metabolite signaling ccf-mtDNA release, mtDNA-encoded
proteins, Krebs cycle metabolic
Paracrine and endocrine effects on
multiple organ systems
MAL = mitochondrial allostatic load; mtDNA = mitochondrial DNA; OXPHOS = oxidative phosphorylation; RC = respiratory chain, also known as the electron transport
chain (ETC); ATP = adenosine triphosphate; ROS = reactive oxygen species; ccf-mtDNA = circulating cell-free mitochondrial DNA.
Psychosomatic Medicine, V 80 126-140 130 February/March 2018
from the stressor towards mitochondrial recalibrations, can be
conceptualized as follows: a) systemic stress mediators cause
mitochondrial structural and functional adaptation (e.g., activa-
tion of hormonal receptors, fusion/fission shape changes, and reac-
tive oxygen species [ROS] production); b) cumulative effects of
stressors eventually damage the mtDNA (e.g., mutations and dele-
tions) and/or induce lasting changes in mitochondrial content and
energy production capacity; and c) mitochondria begin to produce
signals, including mitokines, that influence cellular and systemic
pathophysiological processes involving traditional allostatic load
biomarkers such as lipids and glucose (48), but also other allostatic
changes including gene dysregulation, oxidative stress, inflamma-
tion, and senescence (Fig. 3). Collectively, the structural and func-
tional changes that mitochondria undergo in response to chronic
stressors are thus referred to as MAL (51). Furthermore, the systemic
recalibrations caused by mitochondrial dysfunction may further
feedforward and sustain MAL, as discussed in the section Mito-
chondrial regulation of stress reactivity systems: HPA, SAM, and
Autonomic Nervous System.
MAL is operationalized as the multifactorial alterations of
mitochondrial biology induced by chronic stressors and may in-
volve multiple functional and molecular indicators (see Table 1).
MAL involves both quantitative changes in specific parameters
(e.g., ATP synthesis and ROS production) and qualitative alter-
ations in their physiological functions (e.g., fusion/fission dynam-
ics, preference for fat or carbohydrate substrates, and production
of specific signaling molecules). Both changes in the quantity of
mitochondria per cell and the quality of each mitochondrion may
represent MAL, depending on the stressor and the cell type.
A key distinction between MAL and the traditional allostatic
load index must be noted. Whereas allostatic load biomarkers are
individual molecular entities, such as circulating proteins (i.e.,
cytokines) or metabolites, mitochondria are living symbiotic mi-
croorganisms. A single protein such as a secreted interleukin is
best characterized by its abundance: it can be higher or lower in
concentration. In contrast, living systems, regardless of their
size, are generally best characterized by dynamic measures of their
rhythms and functions (52). Based on this principle, stress-induced
changes in mitochondrial energy production capacity, or ROS
production, will be more accurately reflected by enzymatic
activities measured over a period, rather than by the fixed
amount of specific mitochondrial proteins. In keeping with
the definition of MAL as the collective changes in structure
and functions, MAL should be more precisely quantified with
a combination of measures that reflect and integrate multiple
dynamic functionsor MAL indices. Because mitochondria are
different between cell types and tissues, we may gain in specificity
and sensitivity by developing cell-type-specific MAL indices
for blood leukocytes, buccal cells, muscle, brain, etc. Furthermore,
it is conceivable that certain MAL indices will be most specific
and/or sensitive to certain types or duration of stressors, a question
that remains to be explored.
In the same way that the allostatic load index has evolved sub-
stantiallysince its inception (3,53), MAL measurements are bound
to evolve and become more precise. This evolution will be driven
by three main factors: a) our increasing understanding of various
facets of mitochondrial biology, b) of their relevance to stress
physiology and psychosomatic medicine, and c) by technical
developments that will permit an increasing number of suitable
mitochondrial measures from accessible biological samples (e.g.,
plasma, leukocytes, buccal cells, hairs, etc).
Developing robust MAL measures will enable researchers to
address two major questions: a) What are the effects of psychoso-
cial stress and emotional states on mitochondrial functions?
b) What are the physiological and health consequences of MAL.
Because mitochondria are present in every cell and organ of the
body, MAL can theoretically engender organ-specific effects, as
seen in mitochondrial diseases. The presented framework positions
mitochondria as an integrating element of stress-disease cascade
(Fig. 3, right), lying at the interface of the psychosocial and
behavioral factors and the organism. Research is needed to better
define not only the existing relationships between mitochondria
and the various systems involved in psychosomatic processes,
but also the resulting systemic and organ-specific effects of
MAL. Moreover, stress-induced mtDNA and other damage could
represent a mechanism for the biological embedding(9)ofstressful
experiences at the mitochondrial level. However, empirical
research using longitudinal and prospective study designs will be
necessary to evaluate this possibility, and if proven, to evaluate
its reversibility.
In mapping the relationships between psychosocial exposures
across one's lifetime and MAL, the kinetics of mitochondrial re-
sponses to various stressors should be considered. Mitochondrial
responses to stress may be biphasic. For example, low levels of
glucocorticoids may enhance mitochondrial calcium buffering
but, at high doses, result in decreased calcium-buffering capacity,
excess free radicals generation, and sensitization to cell death
(14). Thus, molecular and functional recalibrations in mitochon-
dria may be best characterized by inverted U-shaped responses
that vary either in kinetics or in amplitude, which reflect resilience
and adaptive (in)capacity of the system (Fig. 4). From a research
design perspective, this underscores the value to measure mito-
chondrial outcomes at multiple time points, and to monitor stress
duration, intensity, and type, which may synergize to cause spe-
cific MAL patterns. The next three sections consider the specific
influence of mitochondria on normal and abnormal functions of
the brain, the neuroendocrine system, and immune regulation.
mtDNA defects cause mitochondrial disease and multiple neuro-
logical symptoms that may preferentially affect the brain (56,57).
In addition, other developmental and age-related neurological
disorders not believed to be of primary mitochondrial origin also
present with underlying mitochondrial dysfunction, including
autism spectrum disorder (58,59) and neurodegenerative condi-
tions such as Alzheimer's and Parkinson's diseases (60,61). In
diseased brain tissue, mitochondrial disorders and neurodegener-
ative conditions share common gene expression signatures, also
suggesting a mechanistic overlap (30,62). In an animal model of
Alzheimer's disease, cognitive and neuropathological symptoms
progression have been prevented with mitochondria-targeted anti-
oxidant therapy (63), providing direct evidence that mitochondrial
defects likely play a primary role in the etiology and progression
of neurodegenerative conditions (64).
Structural changes within the brain, such as those induced
by chronic stress on the hippocampus, may be indicative of
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Psychosomatic Medicine, V 80 126-140 131 February/March 2018
mitochondrial dysfunction. Structurally, patients with primary
mitochondrial disorders frequently present with atrophy of
cerebrocortical, cerebellar, and brainstem regions (65,66), as
well as cerebrovascular disease (67). Genetic studies in animal
models have also shown that mtDNA mutations can influence
brain development (68). Likewise, some but not all (69,70) stud-
ies of the human hippocampus have demonstrated shrinkage of the
hippocampus in mild cognitive impairment and Alzheimer's dis-
ease (71), chronic major depression (72), Cushing's disease
where glucocorticoids are produced in excess (73), and posttrau-
matic stress disorder (74). The hippocampus is not the only brain
region affected. Amygdala enlargement and overactivity, as well
as hippocampal and prefrontal cortical shrinkage, have been re-
ported in a number of mood disorders (72,75). Moreover, psy-
chosomatic conditions that do not qualify as disease,such as
chronic (several years) stress exposure (76), systemic inflamma-
tion associated with metabolic syndrome and underlying oxidative
stress (77,78), lack of physical activity (79), and jet lag (80) have
been associated with smaller hippocampal or tempora l lobe vol-
umes. Although it remains unclear from available research if
mitochondria contribute to these effects on the human brain, ev-
idence that cerebral atrophy is a neurological feature common
to both psychopathology and primary mitochondrial disorders
is consistent with a mitochondrial etiology of stress-induced
brain atrophy.
Experiencing chronic stress evokes in the brain an array of
adaptive responses consisting of neuronal atrophy in the hippo-
campus and medial prefrontal cortex, and expansion of dendrite
of neurons in basolateral amygdala (81). These are adaptive in
the face of danger as they increase vigilance, but at the cost of some
cognitive acuity (82). In a striking similarity to mitochondrial bio-
genesis (i.e., the formation of new mitochondria), neurogenesis is
inhibited by chronic stress and enhanced by exercise (82,83). In
fact, exercise-induced neuronal stem cell expansion, a prerequisite
for neurogenesis within the brain, requires normal mitochondrial
dynamics and involves expansion of mitochondrial content in
the hippocampus (84), underscoring a primary role of mitochon-
drial functions in brain plasticity. In line with this, hippocampal
atrophy and memory decline occur in aging but are prevented
by physical activity (85), similar to the age-related decline in
mitochondrial function that is prevented by physical activity
(86). Together, these correlational data highlight the potential
parallel between exercise/physical activityinduced systemic
changes in mitochondria and those that occur within the brain.
Stress vulnerability is also evident in relation to changes in neu-
ral activity, which entail variations in mitochondrial energy supply
and demand. For instance, dangerous elevations of glucose for
extended periods as in diabetes type 1 and 2 represent a form of
metabolic stress that fragments mitochondria and promote mtDNA
damage (20). In the human brain, excess glucose accelerates
age-related brain atrophy and neurovascular damage, and impairs
neurogenesis (8789). In contrast, in animals, reduced energy
demand during hibernation is also associated with hippocampal
CA3 shrinkage (90,91). Overactivation of the hippocampus in
seizures and ischemia along with elevated glucocorticoid increases
vulnerability to permanent damage, referred to as glucocorticoid
endangerment,whereas reduction of glucocorticoids under these
conditions is protective (9294). In that connection, as mentioned
above, there are biphasic effects of glucocorticoids on mitochondrial
calcium buffering, with high glucocorticoid levels leading to a
failure of the calcium-buffering mechanism and cell death (14).
In addition to structural remodeling, mitochondria also dynam-
ically impact brain function and cognition via specific molecular
and cellular mechanisms (95). In particular, smaller synapses and
impaired working memory in nonhuman primates have been
linked to abnormal presynaptic mitochondrial shape, such as the
conspicuous donut-shaped mitochondria (96). Likewise, in mice,
anxiety-related behavior (97), as well as circadian rhythm (i.e.,
physiological processes that occur within a 24-hour cycle)
and hippocampal-dependent spatial memory, is affected by the
FIGURE 4. Possible inverted U-shaped mitochondrial responses to chronic stress. A, Biphasic mitochondrial stress responses as a form of
mitohormesis (54), as induced by glucocorticoids (e.g., Ref. (14)). The transition from adaptive to maladaptive is marked by the inversion
of the curve at the top. Each line depictsa cellular or physiological system with a different degree of resilience, as indicated by the duration
for which it can sustain an adaptive response to the stressor before undergoing a decline in mitochondrial health below baseline. B, The
adaptive capacity of mitochondria can vary, as indicated by the degree to which they can generate an adaptive increase in function during
stress, depicted hereby the height of curves. C, Certain stressors, particularly during sensitive developmental windows, can also have long-
term programming effects that establish lasting set points (detrimental or protective) for mitochondrial health. For example, antiretroviral
pharmacotherapy for HIV-AIDS may lead to the permanent accumulation of mtDNA defects that undermine respiratory chain function
and decrease baseline function (55). Subsequent exposures (arrows) may have additive effects and further decrease function (below
baseline), as a form of detrimental embedding. On the other hand, positive behavioral exposures such as exercise training can increase
basal mitochondrial function (above baseline), as a form or protective embedding. mtDNA = mitochondrial DNA. Color image is
available only in online version (
Psychosomatic Medicine, V 80 126-140 132 February/March 2018
mtDNA (98). Thus, both morphological and genetic mitochon-
drial anomalies are emerging causes of brain dysfunction. These
are thought tooperate at least in part by promoting the maladaptive
structural and functional changes that the brain undergoes in
response to adverse psychosocial environments throughout de-
velopment (8). In future work, it will be important to determine
if changes in mitochondrial function and MAL precede brain
changes in humans, and if promoting mitochondrial health
may have salutary effects on the brain and cognition.
Connected and downstream from the brain are the hypothalamic-
pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM)
axes, which produce hormones required for the normal stress re-
sponse (99). Preliminary evidence in mice suggests that mtDNA
genetic variants can alter stress-reactive corticosterone production
(35,97), and individuals with an inherited mutation causing mito-
chondrial oxidative stress were found to exhibit adrenal cortex
dysfunction and hypocortisolemia (100). In patients with a genetic
defect impairing mitochondrial ATP transport, resting circulating
catecholamine levels are also elevated to about double the con-
centration in healthy controls (101). These clinical data indicate
that both HPA axis and SAM axis activities may be directly
modulated by mitochondrial function. This question was re-
cently examined experimentally in mouse models with genetic
mitochondrial defects exposed to restraint stress, a model of
psychological stress in rodents (35). This work demonstrated
that mitochondria influence all aspects of the stress response in-
vestigated, including cortisol and catecholamine levels (35), fur-
ther positioning mitochondria as stress response modulators as
depicted in Figure 3.
Likewise, cardiorespiratory and neuroendocrine responses,
which are in part driven by a combination of sympathetic and
parasympathetic autonomic nervous system inputs, are altered
during exercise in patients with mtDNA disorders (102). This
may partly be due to decreased vagus nerve activity both at
rest and during exercise as evidenced by increased resting
heart rate and decreased high-frequency power R-R interval var-
iability in patients with mitochondrial disease (103). Individuals
with mtDNA disorders also have elevated stress-reactive epineph-
rine and norepinephrine release by the SAM axis during an exer-
cise challenge (104), possibly because mitochondrial defects alter
the physiological and/or the psychological/affective perception of
the stressor.
Whether these mitochondria-driven abnormal neuroendocrine
responses to exercise also translate into abnormal responses to
psychosocial stress remains unclear. However, evidence in healthy
individuals suggest that those who exhibit stronger HPA axis re-
sponses to physical activity also show stronger cortisol release to
psychological stress (105), suggesting that a common biological
mechanism regulates the magnitude of responses to stressors of
different nature (physical and psychological). Interindividual dif-
ferences in neuroendocrine responses to psychosocial stressors
also exist between racial and ethnic groups (106). Interestingly,
mtDNA genes vary with ethnicity (107), such that differences
in mitochondrial function could also in part account for
interindividual differences in stress responses. Overall, more
research is needed to examine if differences in mitochondrial
functi ons are at the origin of known interindividual differences
in HPA, SAM, and autonomic nervous system responses to psy-
chological stress in humans.
The immune system exhibits particular sensitivity to psychological
states and related neuroendocrine mediators including catechol-
amines and glucocorticoids (2). Immune cells are also a major
source of inflammatory mediators (108), which feedback onto
the brain and autonomic nervous system, and vice versa (109,110).
Proinflammatory gene expression at the cellular level (e.g., nu-
clear factor κB) and systemic release of pro-inflammatory cyto-
kines (e.g., interleukin 6 [IL-6]) are thus thought to contribute to
the effects of acute and chronic emotional states, both positive
and negative, on health outcomes and other psychosomatic pro-
cesses (111113). Interestingly, discoveries over the last decade
have positioned mitochondria within canonical cellular processes
related to both innate and adaptive immunity (114). The role of
mitochondria on the immune system and inflammation can be
divided into three main categories.
Mitochondria Trigger Inflammation
Because mitochondria are of bacterial origin, their circular
mtDNA and resultant proteins (n-forlmyl peptides) are recognized
as foreign by the immune system. These mitochondrial immu-
nogenic molecules, termed alarminsor damage-associated
molecular patterns, are released under conditions of mitochon-
drial stress, particularly in response to oxidative stress (115). The
release of mitochondria-derived damage-associated molecular
patterns triggers the innate immune system through the intracel-
lular DNA-sensing system cyclic GMP-AMP synthase (116)
and systemically via toll-like receptors (117). In macrophages, ac-
tivation of these systems by mtDNA that leaks outside mitochondria
engages the inflammasome (118), cytokine release, and proinflam-
matory gene expression (119).
In animal models, mitochondria-induced inflammation results
in cardiovascular lesions (120) and has been associated with neuro-
degeneration in humans (121). Interestingly, the anti-inflammatory
signal of acetylcholine may prevent stress-induced release of
mtDNA possibly via binding of a mitochondrial nicotinic ace-
tylcholine receptor (115). Mitochondria-localized proteins encoded
in the nuclear genome such as heat shock protein 60 can also be re-
leased from cells and become detectable in circulating plasma (122).
From a psychosomatic perspective, a noteworthy study conducted
among disease-free workers from the Whitehall II cohort revealed
that circulating heat shock protein 60 levels were correlated with
psychological distress, job demand, and low emotional support, as
well as with cholesterol levels (122), indicating a potential link be-
tween psychosocial factors, mitochondrial stress, and cardiovascular
disease indicators.
Another recently described pro-inflammatory mitochondria-
derived signaling molecule (mitokine) is circulating cell-free
mtDNA (ccf-mtDNA), which consists of mtDNA circulating in
the liquid fraction of blood. Such circulating mitochondrial genome
is either passively released from cellular damage or necrotic death,
Stress and Mitochondria
Psychosomatic Medicine, V 80 126-140 133 February/March 2018
or actively extruded via active secretion from mitochondria; how-
ever, t he exact origin of circulating mitochondrial genome fragments
is unclear. Ccf-mtDNA is found at detectable levels in human plasma
and serum (123), where it likely exists as small genomic fragments
(124). Serum levels are significantly higher than plasma levels, sug-
gesting that mtDNA release is enhanced during coagulation (125),
possibly by platelets. Ccf-mtDNA is particularly abundant in inflam-
matory diseases (123), as well as in cancers, myocardial infarction,
and sepsis where it is a prognostic indicator of disease and mortal-
ity (126128). Strikingly, in hospitalized critically ill individuals,
high ccf-mtDNA levels were associated with a fourfold to eightfold
increased risk in mortality compared with individuals with normal
ccf-mtDNA levels (126). In suicide attempters, ccf-mtDNA
was also found to be dramatically elevated compared with
controls and partially correlated with cortisol levels after
dexamethasone suppression test, suggesting that the psychological
state associated with suicidality might promote the extrusion
of ccf-mtDNA into the blood. In relation to inflammation,
mtDNA amplifies tumor necrosis factor α(TNF-α) release
by lipopolysaccharide-stimulated primary human monocytes,
indicating the immunogenicity of circulating mtDNA in human
leukocytes (129). Besides stimulating inflammation, the role of
mtDNA release as a paracrine or endocrine signals remains to
be determined. Overall, mitokines like ccf-mtDNA are emerging
as a source chronic systemic inflammation, suggesting potential
new biomarkers of early-stage inflammatory processes known to
be related to indicators of psychosocial stress (112).
Mitochondria Are Essential to Innate Immunity
In the cytoplasm of infected immune cells,energized mitochondria
(i.e., with an active membrane potential) recruit the mitochondrial
antiviral signaling protein, which aggregates on the mitochondrial
outer membrane and initiate signaling (130). This process enables
the cellular antiviral response by downstream activation of nuclear
factor κB and interferon regulatory factors, which translocate
to the nucleus to induce the expression of type I interferons and
proinflammatory cytokines genes (130). Ablating mitochondrial
membrane potential inhibits this response (131), whereas mito-
chondrial ROS potentiate it (132), illustrating bimodal mitochon-
drial regulation. Furthermore, as mentioned previously, mtDNA
that leaksinto the cytoplasm can also activate intracellular
DNA receptors such as cyclic GMP-AMP synthase and directly
trigger innate immune response genes independently of any infec-
tion or external stressor (116).
Possibly as a result of the influence of mitochondrial function
on innate immunity, mtDNA variantswhich vary according
to ethic origin (107)not only influence mitochondrial function
but also correlate with metabolic and immune parameters during
antiretroviral therapy (133,134), as well as HIV/AIDS progression
and mortality (135). This modulatory effect of mtDNA on infec-
tious disease progression is believed to result from biochemical
differences in mitochondrial respiratory capacity (136) and is
reminiscent of the modulatory effect of both positive and nega-
tive psychosocial factors, such as social support and depressive
symptoms, on HIV/AIDS disease (137). Mitochondrial regulation
of innate immune responses may thus interact with psychosocial
factors to impact inflammatory responses and vulnerability to
infectious diseases.
Mitochondrial Metabolism Regulates Immune Cell
Differentiation and Inflammatory Phenotype
Activation and quiescence of immune cells involve metabolic
reprogramming where mitochondrial content and function are al-
tered (138). For instance, upon injury, undifferentiated monocytes
actively differentiate into either proinflammatory (M1) or anti-
inflammatory (M2) macrophages. M1 proinflammatory cells rely
mainly on glycolysis for energy production, whereas M2 anti-
inflammatory cells show mitochondrial proliferation and up-
regulation of oxidative metabolism (139). The same is true of
lymphocytes, which cannot adopt specific effector functions
(T regulatory versus memory) without adopting the correct me-
tabolism (114). Not unexpectedly then, mitochondrial dys-
function influences immune phenotypes. For instance, mice with
different mitochondrial genomes exhibit differential suscepti-
bility to experimental autoimmune encephalomyelitis (140),
and infectious complications are a significant clinical concern in
patients with mitochondrial disorders (141).
In relation to stress, mitochondrial immune modulation may
also involve glucocorticoids. Glucocorticoid signaling via the
glucocorticoid receptor (GR) can significantly inhibit proinflam-
matory responses (142), and an important feature of the immune-
endocrine system is glucocorticoid receptor resistance that develops
with chronic stress (e.g., Ref. (143)). Given that glucocorticoids in-
duce GR translocation into mitochondria where it affects mtDNA
gene expression and mitochondrial functions (14), and that the mi-
tochondria are central to immune modulation, GR-mediated sup-
pression of immune cell activation may involve (nongenomic)
mitochondrial mechanisms. The role of mitochondria in glucocor-
ticoid receptor resistance, their role in the chronic low-grade in-
flammatory state that characterizes chronic stress and aging, and
their contribution to psychological stressinduced inflammatory
responses, all remain to be examined. Conclusively resolving these
questions at a mechanistic level will require the combination of ex-
perimental approaches and population-based studies with repeated
measurements of mitochondrial functions in parallel with psychoso-
cial and neuroendocrine factors queried prospectively.
Beyond but related to the immune system, mitochondrial may
also link inflammation to metabolic dysregulation and depression.
There is a specific short-chain lipid molecule, acetyl-L-carnitine
(LAC), which enhances mitochondrial oxidation of substrates
and may protect and enhance mitochondrial function (144). LAC
acts as an acetyl donor for metabolism and for epigenetic mod-
ification of histones (145) and for mitochondrial proteins in a
biphasic manner (146,147). In animal models, LAC deficiency
is associated with metabolic dysregulation, including insulin
resistance and elevated triglycerides and leptin. Like the
depressive-like behavior, this state is rapidly corrected by LAC
treatment (148). Together, this evidence demonstrates that mito-
chondrial metabolism can rapidly remodel both immune and neural
activities, which together influence the activation/deactivation of
stress-response systems at the interface of psychosomatic processes.
Forty years ago, mitochondrial dysfunction, more specifically
mtDNA damage, was postulated to represent the biological aging
clock(149). Other aging clocks have also been proposed including
Psychosomatic Medicine, V 80 126-140 134 February/March 2018
telomere length (150) and DNA methylation (151). Only recently
has evidence unequivocally demonstrated that mitochondria influ-
ence the rate of aging in mammals.With age, the mtDNA accumu-
lates mutations (152). To study this process experimentally, mice
with a faulty proofreading mtDNA polymerase-γthat introduces
random mtDNA mutations at every cycle of mtDNA replication
were generated. These mutatormice accumulate higher-than-
normal mtDNA mutations with concomitant mitochondrial oxida-
tive stress (153) and, as a result, age prematurely, living only up to
approximately half the life-span of their counterparts with normal
mtDNA mutation levels (154,155). The MtDNA mutator mice ex-
hibit multiple signs of advanced human aging including muscle
and brain atrophy, exercise intolerance, whitening of hair, and kypho-
sis (154,155). Interestingly, a study demonstrated that this progeroid
phenotype is entirely avoided by exercise (156), suggesting the poten-
tial for profound modulation of mitochondrial functions and of the
downstream physiological consequences by behavioral factors.
One possible mechanism by which mitochondria accelerate the
aging process is by mitochondria-derived oxidative stress directly
promoting telomere erosion. Mitochondrial ROS can cause
telomere instability and shortening in vitro (157), and prelimi-
nary evidence suggests that individuals with mtDNA mutations
causing mitochondrial disease may have abnormally short telo-
meres in affected tissues (158). A recent study where cultured
cells were depleted of their mitochondria demonstrated that cell
senescence, including the senescence-associated secretory pheno-
type, was prevented in the absence of mitochondria (159). Such
evidence is consistent with the notion that mtDNA defects and
MAL, via the production of signals that reach the cell nucleus, can
trigger organismal aging and senescence, via telomeredysfunction
and possibly other mechanisms.
Because biology rarely operates unidirectionally, mitochondria
and telomeres are in fact bidirectionally linked. Telomere dys-
function resulting from telomerase (hTert) deficiency in mice
effectively decreases mitochondrial content and function, involving
the down-regulation of peroxisome proliferatoractivated receptor-
γcoactivator 1αsignaling and mitochondrial biogenesis (160). Ac-
cordingly, in human blood cells, mtDNA copy number and telomere
length are moderately correlated (r=0.120.56) (161,162), with the
strength of the association being stronger in those having adverse
childhood experiences and with a history of psychopathology (162).
Should this association be replicated in longitudinal and prospective
studies, resolving the mechanisms underlying this specificity in re-
lation to psychological stress would yield important insight into
the role of mitonuclear signaling in human aging.
One common factor proposed to contribute to both telomere
shortening and acceleration of the aging process is inflammation
(163). In one study, genetically enhancing mitochondrial respi-
ratory chain complex I activity in cultured cells simultaneously
increased cellular ATP levels and decreased ROS production.
This mitochondrial phenotype was associated with a concomitant
reduction in lipopolysaccharide-stimulated IL-6 production while
suppressing cell senescence (164). In another study, individuals
previously exposed to early life adversity had their leukocyte mi-
tochondrial respiration measured in parallel with inflammatory
cytokines (165). Results revealed that the basal mitochondrial
respiration relative to their maximal capacity was positively corre-
lated with IL-6, TNF-α, and interleukin 1β(165). This evidence
suggests that cellular metabolism in general, and mitochondrial
respiratory capacity in particular, may influence both inflamma-
tion and cell aging in parallel. If proven true in humans, strategies
to improve mitochondrial function could represent an effective up-
stream countermeasure to prevent the deleterious health effects of
psychosocial adversity and inflammation.
In the same way that telomere shortening is considered to indi-
cate biological age, decreasing mtDNA copy number and increas-
ing tissue mtDNA damage are aging biomarkers (166,167).
mtDNA copy number measured in whole blood (including all cell
populations and contaminating platelets) decreases with advancing
age, starting around 50 years (168). Also starting after the fifth decade
of life, the amount of immunogenic plasma ccf-mtDNA is elevated in
older age groups, in parallel with increases in proinflammatory cyto-
kines TNF-α, IL-6, and interleukin-1 receptor antagonist, suggesting
In muscle of elderly populations, mtDNA copy number and
respiratory capacity also decline with age (169), but these
recalibrations may be attributed to physical inactivity because
exercise training restores several, albeit not all, parameter to
levels of young individuals (170). The accumulation of deletion
of an mtDNA segment (mtDNA deletion) in postmitotic (i.e.,
nondividing, such as the brain, heart, and muscles) tissues is robust
(166), representing a form of MAL. Moreover, as discussed previ-
ously, accumulation of mtDNA defects is promoted by metabolic
stress (20,171). Metabolic stress in the form of hyperglycemia and
hyperlipidemia is also promoted by the action of glucocorticoids
and catecholamines released during psychosocial stress and life
adversity. As a result, stress-induced metabolic stress leading to
mtDNA damage and MAL is a potential mechanism by which ad-
verse psychosocial experiences and chronic negative emotional
states may impair cell energetics and possibly contribute to the
age-related functional decline and increased vulnerability to disease
(51). In blood cells, mtDNA deletions have also been detected in
individuals with coronary artery calcification and cardiovascular
disease (172), representing cross-sectional evidence that MAL is as-
sociated with downstream organ-specific pathology. Thus, mtDNA
defects and particularly mtDNA deletions may represent MAL
markers linked to mitochondrial dysfunction and disease risk.
The study of exposure to chronic stressors and their effects on
aging and life-span have mainly been guided by three general
models, namely, cumulative risk (173,174), stress sensitization
(175,176), and stress buffering (177,178). Table 2 outlines the
parallel between each model in the context of psychosomatic
medicine, with parallel facets of mitochondrial biology. These
include the accumulation of mtDNA damage over time, the
stress-sensitizing effects of mitochondrial dysfunction causing
abnormal HPA and SAM axes responses to challenge, and the
role of energetic capacity in buffering against certain types of
stressors. In relation to aging and geroscience, mitochondrial
dysfunction is thus considered one of the hallmarksor pillars
of aging (179), which interact broadly with other biological factors
that collectively shape aging trajectories.
It is with the vision to reintegrate psyche and soma that the first
edition of Psychosomatic Medicine was published in 1939 (4).
The field evolved from the concept of milieu intérieur(Claude
Bernard, 18131878), subsequently built from understanding
Stress and Mitochondria
Psychosomatic Medicine, V 80 126-140 135 February/March 2018
how emotional states led to physiological perturbations (Walter
Cannon, 18711945), and the discovery that chronic stress could
alter organ structure and their function (Hans Selye, 19071982).
With time, statistical methods have become increasingly refined,
whereas larger and more sophisticated study designs have been
elaborated to extract causal relationships between variables. More
recently, increasingly precise biomarkers have been identified and
applied to extend the reach of mind-body research into the cellular-
molecular domain that is the core foundation of current biomedical
training and practice.
Historically, it has been noted that progress within individual
fields of investigation can be hindered by a lack of understanding
of the relationships across fields (180). Conversely, identifying
and studying intersection points between fields,focusing on differ-
ent levels of function ranging from molecules to systems, has con-
tributed to further the development of psychosomatic medicine.
This is exemplified by foundational work in PNI and the discov-
ery of intersection points between the immune system and the
brain (99). Subsequent work on glucocorticoid hormones, cate-
cholamines, and inflammatory cytokines, which carry information
between various organ systems, considerably expanded our under-
standing of the interrelations between physiological systems, their
activation by stress, and the role of brain remodeling in disease
(8,112,181). The allostatic load model describing the impact of
chronic stress and resultant health behaviors has been particu-
larly productive in providing a quantifiable (182) and integra-
tive perspective of multisystemic physiological dysregulation
in response to chronic stress and adversity (183). At the cellular
level, the discoveries that the rate of telomere shortening is modi-
fied by stress (184) and that gene expression is subject to social
modulation (185) have likewise spurred new depth into the biol-
ogy of subjective experiences.
Importantly for the general mandate of psychosomatic medi-
cine, these molecular findings resonate with the subcellular focus
of the biomedical model. Discoveries of novel biomarkers that dy-
namically respond to emotional states help to establish a common
semantic and conceptual basis for discussion among psychosocial
and medical scholars. This contributes to building common
transdisciplinary knowledge and is of value to all scientists
invested in constructing a comprehensive, or holistic understand-
ing of human health and disease processes. While keeping in
mind the whole individual, identifying increasingly refined bio-
logical intersections points, including mitochondria, should
therefore continue to uncover new layers of complexity onto
which we can observe,measure,andquantify the cross-talk be-
tween psycheand soma.
One of the objectives for psychosomatic research is to under-
stand the basis for stress pathophysiology. How do adverse and
positive life experiences leave biological marks, and influence
trajectories of aging and disease risk? In considering the role of
mitochondria in this process, evidence discussed above and sum-
marized in Figure 3 indicates that mitochondria represent a po-
tential biological intersection point that could contribute to
multiple domains of stress pathophysiology. The proposed frame-
work suggests that chronic psychosocial stressors and related
emotional states lead to dysfunctional mitochondria and MAL,
which in turn contribute to stress pathophysiology via multiple
mechanisms including changes in gene expression and the epige-
nome, alterations of brain structure and functions, and abnormal
stress reactivity, inflammation, and by promoting cellular aging.
More research is needed to test various elements of this model,
particularly in humans. Furthermore, although compelling evidence
reviewed here positions mitochondria as a nexus for various stress-
and aging-related processes, future research should consider the
dynamic bidirectional interactions between mitochondria and other
important physiological systems.
Mitochondrial biology is deeply interlaced with the basic mo-
lecular and physiological principles onto which lies medical prac-
tice and education. Exploring different facets of mitochondrial
function and MAL in psychosomatic research should therefore
provide new insights directly linked to biomedical knowledge,
and hopefully contribute to the bridging enterprise with medicine.
To do so, mitochondrial functions and related aspects of cellular
bioenergetics should be investigated with the proper methodology,
using prospective and longitudinal study designs whenpossible, in
parallel with established neuroendocrine and molecular biomarkers
TABLE 2. Parallel Comparison Between Theoretical Models Guiding Psychosocial Investigation of Stress Pathophysiology, and
Biological Concepts Relevant to Mitochondrial Function
PsychosocialTheoretical Models MitochondrialBiological Concepts
Cumulative risk
Damage accumulates over time, eventually reaching
athreshold where dysfunction and/or senescence
compromises physiological regulation.
Mitochondria accumulate mtDNA defects with age
and metabolic stress, eventually reaching a
functional threshold where energy production and
other bioenergetic functions become compromised.
Stress sensitization
Stressors becomes increasingly likely to cause
damage or dysregulation under specific adverse
circumstances or over time.
Organisms with inherited or acquired mitochondrial
defects exhibit exaggerated and abnormal responses
to subsequent stressors.
Stress buffering
Psychosocial resources (e.g., social support and
self-efficacy) and behavior (e.g., exercise) confer
protection against the deleterious effects of
chronic stress.
Up-regulation of mitochondrial content, mitochondrial
networking, and mitochondrial antioxidant defenses
increases overall mitochondrial function and as a
result promotes cellular resilience to insults.
mtDNA = mitochondrial DNA.
Psychosomatic Medicine, V 80 126-140 136 February/March 2018
known to be responsive to stress and other psychosocial factors.
This integration of concepts and approaches will ensure a synergy
with existing research and methodologies, promote collabora-
tion, and enable us to map new pathways by which stress gets
under the skin,all the way into the genome.
Integrating the many rich concepts and approaches from psy-
chosomatic medicine, PNI, and psychoneuroendocrinology with
mitochondrial biology under a common psycho-mito-somatic
framework should enable us to systematically map the effects of
psychological stress and other psychological states on mitochon-
dria. Examining the resulting mitochondrial recalibrations and
their downstream correlates should then inform us on the effects
of acquired mitochondrial defects and MAL on important physio-
logical, behavioral, and health outcomes. Ultimately, the suc-
cessful integration of mitochondria in psychosomatic research
should foster a more comprehensive understanding of the forces
that influence our health across the life-span and of the factors
that hinder our ability to heal from disease. Psycho-mito-
somatic studies will hopefully illuminate novel mechanisms for
mind-body interactions and form the empirical foundation to de-
velop higher-level health-promoting interventions based on the
principles of allostasis and bioenergetics.
The authors are grateful to Claudia Trudel-Fitzgerald and
Richard Sloan for comments and thoughtful edits to this article.
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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Psychosomatic Medicine, V 80 126-140 140 February/March 2018
... Various effects of stress can be depression, anxiety, low self-esteem, among others as in Cushing syndrome (22,23). Diet can improve anxiety and depression (24) -but, also, stress can influence food choice (25); the psychologicalemotional state can modulate the function of the immune system (26), and stress can even influence mitochondrial activity (27,28). We can, therefore, speculate, that these mechanisms are involved in the possible bi-directional correlation between depression, anxiety, low self-esteem and global metabolic parameters, as the glycemic homeostasis. ...
Objective: We analyzed the possible correlation between glycemic variability and psychological disorders such as depression, anxiety disorder, and low self-esteem, in diabetic patients. These correlations are relevant, as they consume a large number of resources. Their better understanding can increase the effectiveness of incident reduction techniques and could provide better management and cost reduction of care. Methods: We compared the relationships between the glycemic variability (for a period of 10 days prior to completing the depression questionnaire) and the results of two standardized questionnaires: Hamilton anxiety scale - HRSA (group 1: 500 patients), Rosenberg self-esteem test (group 2: 490 patients) and Beck depression inventory (both groups). Results: A statistically significant correlation was identified between the glycemic oscillation and depression as well as both anxiety and low self-esteem. The present data justify further research. Our results could be developed into a preliminary intervention protocol, using the daily glycemic values measurements, collected by patients. In conclusion, psychometric tests could be an important instrument in the management of diabetic patients.
... Inadequate mitochondrial synthesis of adenosine triphosphate in response to stress will lead to altered energy release, thus altered cellular reactions, such as gene expression, chromatin remodeling, intra/extra-cellular signaling, ion homeostasis, muscle contraction, protein and hormone synthesis and secretion, and neurotransmitter release and reuptake [59]. ...
... Inadequate mitochondrial synthesis of adenosine triphosphate in response to stress will lead to altered energy release, thus altered cellular reactions, such as gene expression, chromatin remodeling, intra/extra-cellular signaling, ion homeostasis, muscle contraction, protein and hormone synthesis and secretion, and neurotransmitter release and reuptake [59]. ...
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Since the prevalence of heart failure (HF) increases with age, HF is now one of the most common reasons for the hospitalization of elderly people. Although the treatment strategies and overall outcomes of HF patients have improved over time, hospitalization and mortality rates remain elevated, especially in developed countries where populations are aging. Therefore, this paper is intended to be a valuable multidisciplinary source of information for both doctors (cardiologists and general physicians) and pharmacists in order to decrease the morbidity and mortality of heart failure patients. We address several aspects regarding pharmacological treatment (including new approaches in HF treatment strategies [sacubitril/valsartan combination and sodium glucose co-transporter-2 inhibitors]), as well as the particularities of patients (age-induced changes and sex differences) and treatment (pharmacokinetic and pharmacodynamic changes in drugs; cardiorenal syndrome). The article also highlights several drugs and food supplements that may worsen the prognosis of HF patients and discusses some potential drug–drug interactions, their consequences and recommendations for health care providers, as well as the risks of adverse drug reactions and treatment discontinuation, as an interdisciplinary approach to treatment is essential for HF patients.
... 27 Allostatic load also has been found to affect function of the mitochondria and has been linked to the mechanism of psychosomatic disorders. 28,29 Note: By the time of completion of the study, we had numerous patients complaining of hair loss due to COVID-19 infection and also from COVID vaccination. Both these situations cause allostatic load on the cells, and the authors have recorded control of hair fall and restoration of hair growth with the same nutritional support as mentioned above. ...
... Due to the limited cardiac regeneration (Bishop et al., 2021), the developmental programming of heart mitochondrial function during a GDM-pregnancy can affect the cardiometabolic signaling throughout offspring life. Several methodologies can be used for assessing mitochondrial function, providing different parameters with complementary information, for review please read (Brand et al., 2013;Gnaiger & MitoEAGLE Task Group, 2019;Picard & McEwen, 2018). ...
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Read-only version at -------- Cardiovascular disease (CVD) is the biggest killer worldwide, composing a major economic burden for health care systems. Obesity and diabetes are dual epidemics on the rise and major risk factors predisposing for CVD. Increased obesity- and diabetes-related incidence is now observed among children, adolescents, and young adults. Gestational diabetes mellitus (GDM) is the most common metabolic pregnancy disorder, and its prevalence is rapidly increasing. During pregnancies complicated by GDM, the offspring are exposed to a compromised intrauterine environment characterized by hyperglycemic periods. Unfavorable in utero conditions at critical periods of fetal cardiac development can produce developmental adaptations that remodel the cardiovascular system in a way that can contribute to adult-onset of heart disease due to the programming during fetal life. Epidemiological studies have reported increased cardiovascular complications among GDM-descendants, highlighting the urgent need to investigate and understand the mechanisms altered during fetal development of in utero GDM-exposed offspring that predispose an individual to increased CVD during life. In this manuscript, we overview previous studies in this area and gather evidence linking GDM and CVD development in the offspring, providing new insights on novel mechanisms contributing to offspring CVD programming by GDM, from the role of maternal-fetal interactions to their impact on fetal cardiovascular development, how the perpetuation of cardiac programming is maintained in postnatal life, and advance the intergenerational implications contributing to increased CVD premature origin. Understanding the perpetuation of CVD can be the first step to manage and reverse this leading cause of morbidity and mortality.
Metabolomics has emerged as a powerful new tool in precision medicine. No studies have yet been published on the metabolomic changes in cerebrospinal fluid (CSF) produced by acute endurance exercise. CSF and plasma were collected from 19 young active adults (13 males and 6 females) before and 60 min after a 90‐min monitored outdoor run. The median age, BMI, and VO2 max of subjects was 25 years (IQR 22–31), 23.2 kg/m2 (IQR 21.7–24.5), and 47 ml/kg/min (IQR 38–51), respectively. Targeted, broad‐spectrum metabolomics was performed by liquid chromatography, tandem mass spectrometry (LC–MS/MS). In the CSF, purines and pyrimidines accounted for 32% of the metabolic impact after acute endurance exercise. Branch chain amino acids, amino acid neurotransmitters, fatty acid oxidation, phospholipids, and Krebs cycle metabolites traceable to mitochondrial function accounted for another 52% of the changes. A narrow but important channel of metabolic communication was identified between the brain and body by correlation network analysis. By comparing these results to previous work in experimental animal models, we found that over 80% of the changes in the CSF correlated with a cascade of mitochondrial and metabolic changes produced by ATP signaling. ATP is released as a co‐neurotransmitter and neuromodulator at every synapse studied to date. By regulating brain mitochondrial function, ATP release was identified as an early step in the kinetic cascade of layered benefits produced by endurance exercise.
Exposure to chronic adverse conditions, and the resultant activation of the neurobiological response cascade, has been associated with an increased risk of early onset of age-related disease and, recently, with an older biological age. This body of research has led to the hypothesis that exposure to stressful life experiences, when occurring repeatedly or over a prolonged period, may accelerate the rate at which the body ages. The mechanisms through which chronic psychosocial stress influences distinct biological aging pathways to alter rates of aging likely involve multiple layers in the physiological-molecular network. In this review, we integrate research using animal, human, and in vitro models to begin to delineate the distinct pathways through which chronic psychosocial stress may impact biological aging, as well as the neuroendocrine mediators (i.e., norepinephrine, epinephrine, and glucocorticoids) that may drive these effects. Findings highlight key connections between stress and aging, namely cellular metabolic activity, DNA damage, telomere length, cellular senescence, and inflammatory response patterns. We conclude with a guiding framework and conceptual model that outlines the most promising biological pathways by which chronic adverse conditions could accelerate aging and point to key missing gaps in knowledge where future research could best answer these pressing questions.
Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABAA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABAA receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.
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Environmental disasters, pandemics, and other major traumatic events such as the Covid-19 pandemic or war contribute to psychosocial stress which manifests in a wide range of mental and physical consequences. The increasing frequency and severity of such events suggest that the adverse effects of toxic stress are likely to become more widespread and pervasive in the future. The allostatic load (AL) model has important elements that lend themselves well for identifying adverse health effects of disasters. Here we examine several articulations of AL from the standpoint of using AL to gauge short- and long-term health effects of disasters and to provide predictive capacity that would enable mitigation or prevention of some disaster-related health consequences. We developed a transdisciplinary framework combining indices of psychosocial AL and physiological AL to produce a robust estimate of overall AL in people affected by disasters and other traumatic events. In conclusion, we urge researchers to consider the potential of using AL as a component in a proposed disaster-oriented human health observing system.
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Objective: Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function. Methods: A systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted. The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria. Results: A total of 23 studies met the inclusion criteria. All studies involved male laboratory animals, and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function, particularly within the brain. Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress. In humans, only six observational studies were available, none with experimental designs, and most only measured biological markers that do not directly reflect mitochondrial function, such as mitochondrial DNA copy number. Conclusions: Overall, evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria. Limitations of current animal and human studies are discussed. Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load. Prospective studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors, emotional states, the resulting neuroendocrine and immune processes, and mitochondrial energetics relevant to mind-body research in humans.
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Insight into the regulation of complex physiological systems emerges from understanding how biological units communicate with each other. Recent findings show that mitochondria communicate at a distance with each other via nanotunnels, thin double-membrane protrusions that connect the matrices of non-adjacent mitochondria. Emerging evidence suggest that mitochondrial nanotunnels are generated by immobilized mitochondria and transport proteins. This review integrates data from the evolutionarily conserved structure and function of intercellular projections in bacteria with recent developments in mitochondrial imaging that permit nanotunnel visualization in eukaryotes. Cell type-specificity, timescales, and the selective size-based diffusion of biomolecules along nanotunnels are also discussed. The joining of individual mitochondria into dynamic networks of communicating organelles via nanotunnels and other mechanisms has major implications for organelle and cellular behaviors.
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Mitochondrial DNA (mtDNA) has many similarities with bacterial DNA because of their shared common ancestry. Increasing evidence demonstrates mtDNA to be a potent danger signal that is recognised by the innate immune system and can directly modulate the inflammatory response. In humans, elevated circulating mtDNA is found in conditions with significant tissue injury such as trauma and sepsis and increasingly in chronic organ-specific and systemic illnesses such as steatohepatitis and systemic lupus erythematosus. In this review, we examine our current understanding of mtDNA-mediated inflammation and how the mechanisms regulating mitochondrial homeostasis and mtDNA release represent exciting and previously under-recognised important factors in many human inflammatory diseases, offering many new translational opportunities.
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Cell free DNA (cfDNA) has received increasing attention and has been studied in a broad range of clinical conditions. However, few studies have focused on mitochondrial DNA (mtDNA) in the cell free form. We optimized DNA isolation and sequencing library preparation protocols to better retain short DNA fragments from plasma, and applied these optimized methods to plasma samples from patients with sepsis. Our methods can retain substantially shorter DNA, resulting in an average of 11.5 fold increase in short DNA fragments yield (DNA <100bp). We report that cf-mtDNA in plasma is highly enriched in short-size cfDNA (30~60 bp). Motivated by this unique size distribution, we size-selected short cfDNA, which further increased the mtDNA recovery rate by an average of 10.4 fold. We then detected mtDNA heteroplasmy in plasma from 3 patients. In one patient who previously received bone marrow transplantation, different minor allele frequencies were observed between plasma and leukocytes at heteroplasmic sites, consistent with mixed-tissue origin for cfDNA. For the other two patients, the heteroplasmy pattern is also different between plasma and leukocyte. Our study shed new lights into the architecture of the cfDNA, and mtDNA heteroplasmy identified in plasma provides new potential for biomarker discovery.
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A recent study by Wiley, Gruenewald, Karlamangla, and Seeman modeling multisystemic allostatic load (AL) was published in Psychosomatic Medicine. The observations reported in this article are consistent with the accumulating evidence published in this journal supporting the role of ad- ditive dysregulated biological and physiological processes in a wide range of diseases. We applaud this article and, here, with the objective of identifying proximal biological processes underlying AL, examine these findings in connection with cellular and mitochondrial biology.
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Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14–3.11] and 2.55[1.26–5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.
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Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging.
Both positive (e.g., happiness) and negative (e.g., anxiety) emotions have been distinctively associated with health and disease outcomes. However, whether emotion-related effects are driven by specific emotions or by shared underlying features of similar co-occurring (or mixes of) emotions is still debated. This narrative review summarizes recent scientific advances regarding whether mixed emotions and emotion regulation abilities influence physical health over the lifecourse. While behavioral and biological pathways are commonly proposed to explain these relationships, biological pathways are less well understood. As a result, here we specifically focus on known and novel biological pathways. Future directions for empirical and clinical research aimed at identifying ways to lower the risk of and burden related to chronic diseases are also discussed.
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.