Integrative and Comparative Biology
Integrative and Comparative Biology, volume 53, number 4, pp. 597–608
doi:10.1093/icb/ict028
Society for Integrative and Comparative Biology
SYMPOSIUM
Energy-Limited Tolerance to Stress as a Conceptual Framework to
Integrate the Effects of Multiple Stressors
Inna M. Sokolova1
Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
From the symposium ‘‘Physiological Responses to Simultaneous Shifts in Multiple Environmental Stressors: Relevance in
a Changing World’’ presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7,
2013 at San Francisco, California.
1
Email: [email protected]
Synopsis Integrating the effects of multiple stressors and predicting their consequences for the species’ survival and
distribution is an important problem in ecological physiology. This review applies the concept of energy-limited tolerance
to stress to develop bioenergetic markers that can assist in integrating the effects of multiple stressors and distinguishing
between the moderate stress compatible with long-term survival of populations and bioenergetically unsustainable extreme stress. These markers reflect the progressive decline of the aerobic scope of an organism (defined as the fraction of
the energy flux and metabolic power supporting this flux available after the basal maintenance costs of an organism are
met) with increasing levels of the environmental stress. During the exposure to moderate stress (i.e., in the pejus range of
the environmental conditions), the aerobic scope is positive but reduced compared with the optimum conditions. The
reduction of the metabolic scope can be due to the (1) elevated costs of basal metabolism, (2) activation of the mechanisms for protection and damage repair, (3) reduced assimilation of food, and/or (4) stress-induced impacts on the
aerobic pathways producing ATP. This leads to suboptimal growth and reproductive rates in the pejus range of environmental conditions and is commonly observed in food-limited and energy-limited wild populations. The tolerance
windows of the organisms are delimited by the pessimum range(s) of environmental conditions in which the aerobic
scope of the organism disappears (so that all available energy and metabolic capacity are used in support of basal
metabolism), energy resources are depleted, and partial anaerobiosis and/or metabolic rate depression set in. The habitats
where environmental conditions remain in the pessimum zone long enough to prevent consistent growth and reproduction often coincide with the species’ distributional limits. Thus, focus on the bioenergetic effects of environmental
stressors and their immediate consequences for fitness provides a suitable framework for integrating physiology and
functional ecology and can assist in understanding the driving forces and limitations of environmental adaptation and
improving assessment of ecological risk as well as environmental management in field populations facing multiple
stressors.
Introduction
Most organisms (with the notable exception of those
from very stable environments such as the deep sea)
live in a dynamic, labile environment where several
important factors can change rapidly and simultaneously. These natural environmental fluctuations
are superimposed with, and exacerbated by, an increasing degree of anthropogenic impacts including
pollution, habitat destruction, ocean acidification,
and global climatic change. When one or more environmental factors deviate from the species-specific
and population-specific optimum, it can lead to
physiological disturbance and a decrease in fitness
and thus is classified as stress—an environmental
factor that causes a potentially injurious change to
a biological system with major impacts on evolutionary processes (Hoffmann and Parsons 1994). Studies
of tolerance of environmental stress and adaptation
to it led to significant advances in our understanding
of the molecular, cellular, and physiological mechanisms of responses to a variety of environmental
stressors including hypoxia, temperature, salinity,
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598
desiccation, ultraviolet radiation, and pollution
(Willmer et al. 2000; Hochachka and Somero
2002). However, the interactive effects of multiple
stressors under environmentally realistic scenarios
are not yet fully understood. Different stressors that
have different physiological and molecular mechanisms can interact in a complex, non-linear way, so
that the effects of combined exposures cannot be
predicted from the effects of single stressors.
Therefore, it is critical to develop an integrative
physiological platform from which to assess and predict the effects of multiple stressors in natural
populations.
Studies of the interactive effects of multiple environmental stressors pose logistic and conceptual
challenges. First, analyses of the effects of multiple
stressors require complex factorial experimental designs that can become logistically impractical as the
number of analyzed stressors increases. Therefore,
the possible stressors need to be screened and
ranked according to their potential physiological
and ecological impacts. Ranking of stressors can be
achieved by multivariate analyses that partition physiological variation among different environmental
variables. These include principal component analysis, multivariate regressions, or artificial neural networks (ANNs) analysis; such studies are still
relatively rare, but their results are encouraging by
revealing that the majority of physiological variation
in natural populations is explained by a relatively
small suite of environmental factors (James and
McCulloch 1990; Lek and Guégan 1999; Chapman
et al. 2011). In some cases, ranking of variables can
be assisted by a priori knowledge of the stressor’s
importance (such as the known effects of individual
stressors and the magnitude of their environmental
variation). For example, temperature is a key environmental factor that affects the physiology, behavior, and ecology of all organisms, particularly
ectotherms, and strongly modifies the effects of
other stressors (Schulte 2007; Sokolova and Lannig
2008; Pörtner 2012), making it advisable to consider
environmental temperature in all studies of the
effects of multiple stressors in natural populations.
It is also important to develop an experimental
approach that allows synthesis of the combined effects of multiple stressors on different physiological
and molecular mechanisms. Focusing on wholeorganism effects (such as survival, growth, and
reproductive output) is a common approach that
provides the advantage of directly translating the effects of stressors into the fitness consequences for an
organism and survival of its populations. However,
such ‘‘black box’’ approaches provide no insight into
I. M. Sokolova
the mechanisms of the effects of multiple stressors
and thus limits our ability to extrapolate the results
to other organisms or other combinations of the
same stressors. To effectively address this challenge,
it is important to develop a mechanistic framework
that allows integrating the effects of multiple stressors with disparate cellular mechanisms and provides
a link between the physiological effects and ecological
consequences of exposure to multiple stresses. Global
molecular and biochemical approaches (such as genomics, transcriptomics, proteomics, and metabolomics) provide important insights into the molecular
mechanisms of the action of multiple stressors, including stressors’ synergy, cross-tolerance, and crosstalk (Chapman et al. 2011; Tomanek 2011; Connor
and Gracey 2012). However, these molecular changes
are often difficult to translate directly into the
changes of the fitness of the whole organism.
Recently, integrative approaches focusing on bioenergetics have been proposed to assess the effects and
ecological consequences of environmental stress
(Pörtner 2010; Sokolova et al. 2012). One of the
most comprehensive physiological models that link
bioenergetic mechanisms to response to stress is
the oxygen-limited and capacity-limited thermal tolerance (OCLTT) concept (Pörtner 2010, 2012). This
model serves as a basis for a recently proposed concept of energy-limited tolerance to stress (Sokolova
et al. 2012) that merges physiological (i.e., OCLTT;
Pörtner 2012) and ecological (i.e., the dynamic
energy budget [DEB] model; Kooijman 2010)
models of response to stress and provides a framework for linking physiological responses to different
stressors and long-term, population-level consequences. In this review, I propose the concept of
energy-limited tolerance to stress as a platform for
integrating the effects of multiple stressors and I
identify bioenergetic markers of the ecologically relevant physiological changes in response to environmental shifts. This review is focused on aquatic
ectotherms because many studies of the bioenergetic
effects of multiple stressors have been conducted on
this group (Heugens et al. 2001; Sokolova and
Lannig 2008; Altshuler et al. 2011; Pörtner 2012;
Sokolova et al. 2012); however, the general principles
of the proposed bioenergetic framework are applicable to other organisms.
Energy metabolism as an integrator of
the effects of multiple stressors
Bioenergetics plays a central role in the tolerance to
environmental stress. For thermodynamically open
living systems, a balance between the input and
Bioenergetics in stress tolerance
expenditure of energy is a key requirement for existence; at the organismal level, this requirement translates into the need for sufficient energy supply to
cover the costs of basal maintenance (i.e., survival),
as well as other fitness-related functions such as activity, growth, and reproduction. The rate of intake
and assimilation of energy, as well as the metabolic
capacity to convert ingested food to ATP, are inherently limited in any organism and are subject to a
metabolic cost (Guderley and Pörtner 2010). This
leads to trade-offs between allocations of energy
and metabolic power to different energy-dependent
functions and requires optimization of these allocations in ways that maximize Darwinian fitness
599
(Kooijman 2010). The optimal allocation of energy
in the absence of environmental stress implies that
the aerobic scope of an organism (defined as the
fraction of the energy flux and metabolic power
available after basal maintenance costs of an organism are met) is at the species-specific and life-stagespecific maximum allowing for maximal investment
into development, activity, somatic and gonadal production, and deposition of energy reserves (Fig. 1A).
Environmental stress can affect the optimal allocation of energy by modulating energy demands for
survival, as well as capacities for assimilation and
conversion of energy, thereby decreasing the aerobic
scope (Fig. 1B–F). When an environmental variable
Fig. 1 The concept of energy-limited tolerance to stress as a framework for assessing the effects of multiple environmental stressors.
Energy-demanding functions are shown on the left side of each scale and are composed of (bottom to top): basal maintenance (green),
activity (yellow), reproduction/maturation (dark red), growth/development (light blue), and deposition of energy reserves (dark blue).
Relative allocation of energy to different energy-demanding processes is variable among species and life stages but sizes of the
corresponding boxes do not reflect the actual energy allocation of energy. ATP for these processes is provided via aerobic (tan) and
anaerobic (brown) metabolism shown on the right-hand side on each scale. In the optimum range (A), the aerobic scope is maximal
and aerobic ATP supply is sufficiently high to cover the basal metabolic costs (BMR) and to invest in activity, growth, reproduction, and
development. The excess of energy is deposited in storage compounds such as glycogen or lipids. During moderate stress in the pejus
range, the maintenance costs increase and meet the demands for additional energy for protection from stress and for repairing damage
(B), or (depending on the stressor) assimilation of food and/or capacity for aerobic metabolism are impaired (C) leading to a decline in
aerobic scope. Energy storage is absent or reduced under these conditions. During extreme stress in the pessimum range, the
progressive increase in ATP demand for maintenance and/or the progressive impairment of aerobic metabolism overrides ATP supply
via aerobic metabolism (D). Aerobic scope disappears, and metabolism switches to partial anaerobiosis that fuels the essential maintenance costs and supports the time-limited survival of the organism. In some species, survival in the pessimum range can be enhanced
by a metabolic rate depression (E) that reduces rates of energy turnover at the expense of shutting down the ATP-demanding functions
that are not essential for immediate survival. It is worth noting that energy balance is temporarily disrupted during transitions between
the optimum, pejus, and pessimum ranges but is eventually reinstated as the organism becomes acclimated/acclimatized to these
conditions. In the lethal range of environmental conditions (F), the balance of supply and demand of ATP is permanently disrupted,
resulting in negative aerobic scope and ultimate death of the organism; this occurs in the presence or absence of metabolic arrest. The
pejus range corresponds to moderate stress, and the pessimum and lethal ranges to extreme stress. Long-term survival of the
population is possible only in the optimum and pejus ranges, although temporary transitions into the pessimum range can be tolerated,
provided that the duration of time that an organism spends under the optimum and pejus conditions is sufficient to allow for
development, growth, and reproduction.
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deviates from the optimum, the aerobic scope of an
organism diminishes due to increased costs of basal
maintenance, limitation of the uptake and delivery
systems of oxygen, reduced capacity for acquisition
of energy, and aerobic ATP synthesis, or a combination of these factors. Depending on the factor and a
degree of its deviation from the population-specific
optimum, the mechanisms responsible for a decrease
in aerobic scope can differ. For example, a decrease
in aerobic scope in response to warming is brought
about by the limited capacity of circulation and ventilation systems to meet elevated demand for oxygen
by tissues (Pörtner 2010), whereas a reduction of
aerobic scope in the cold may be brought about by
the low capacity of mitochondria for synthesis of
ATP (Sommer and Pörtner 2002; Pörtner et al.
2007), and in extreme cases, by cessation of circulation induced by freezing (Storey and Storey 1988).
Moderate concentrations of trace metals such as cadmium reduce the aerobic scope due to a combination of elevated demand of energy for protection
from stress and repair of damage, and reduced mitochondrial efficiency (Lannig et al. 2006; Sokolova
and Lannig 2008; Kurochkin et al. 2011). In contrast,
acutely toxic levels of trace metals can reduce the
aerobic scope by limiting oxygen uptake due to
damage to the gills and to severe impairment of mitochondrial function (Sokolova and Lannig 2008).
Hypoosmotic stress can lead to elevated energetic
costs of homeostasis of ions and water, regulation
of cell volume, and/or repair of damage (Hawkins
and Hilbish 1992; Nelson et al. 1996; Kidder et al.
2006). Hypoxia directly affects the aerobic scope of
an organism due to limited availability of oxygen
and/or elevated demand of energy for enhanced ventilation (Jackson 2007; Nilsson et al. 2010; Pörtner
2010). Regardless of the exact physiological mechanisms, a decrease in aerobic scope results in a reduction of the energy flux devoted to production and/or
to activity, and it can negatively affect the organism’s
fitness.
According to the OCLTT concept (Pörtner 2012)
and the energy-limited concept of tolerance to stress
(Sokolova et al. 2012), the ability to maintain positive aerobic scope is a key determinant in long-term
survival of organisms and sustainability of their populations. Under moderate stress (in the pejus range;
Fig. 1B and C), aerobic scope is reduced but remains
positive so that the long-term survival of the population is possible, albeit at the cost of reduced growth
and reproduction. As the environmental factor further deviates from the optimum, the aerobic scope of
the organism continues to decline until it reaches
zero in the pessimum environmental range (Fig. 1D
I. M. Sokolova
and E). Under these conditions, all energy flux and
metabolic capacity of the organism is devoted to
basal maintenance (i.e., survival), and anaerobic metabolism is often engaged to compensate for the insufficient aerobic production of ATP (Pörtner 2012).
Some species from extremely variable environments
(e.g., intertidal zone, arid, or ephemeral habitats)
have evolved a capacity for metabolic rate depression
that can be engaged in the pessimum range (Fig. 1E).
Metabolic rate depression extends survival time,
thereby increasing the chances that an organism
stays alive until conditions improve (Guppy and
Withers 1999), but it does not increase the aerobic
scope so that time-limited survival is achieved at the
expense of reproduction, growth, and activity. A further increase in environmental stress eventually
results in the aerobic scope becoming negative, and
the energy supply from both aerobic and anaerobic
pathways is insufficient to cover even the basal metabolic demand (Fig. 1F). Under these conditions
(i.e., the lethal range), massive disturbances of
homeostasis, as well as cellular and systemic damages, ensue such that cannot be repaired and result
in morbidity and mortality.
The proposed energy-limited model of tolerance
to stress assumes that basal maintenance (i.e., the
energy demand for survival) takes priority over
other processes, including growth, reproduction, or
storage. This principle has been shown to hold true
for many species (Wieser et al. 1988; Guppy and
Withers 1999; Rombough 2007; Kooijman 2010);
however, under some environmental conditions
and/or at some stages of the life cycle, priorities for
the investment of energy can change. For example,
during breeding semelparous species preferably invest
energy into the functions supporting reproduction
(Stearns 1992; Farrell et al. 2008; Fisher and
Blomberg 2011). Thus, during spawning migrations,
Pacific salmon protect their aerobic scope for swimming at the expense of wastage of the muscles that
eventually leads to death (Farrell et al. 2008).
Similarly, semelparous octopods use their somatic
mass to fuel reproduction and die after a short
period of intensive parental care (O’Dor and Wells
1978). Short-term shifts in the priorities of investment of energy between reproduction and maintenance also are observed during the spawning
season in broadcast-spawning marine bivalves
(Cheung 1993; Li et al. 2007; Petes et al. 2008 and
references therein). It has also been proposed that
similar prioritization of investment of energy into
reproduction over maintenance (so-called terminal
allocation) can occur in older individuals reaching
the limit of their life spans; however, this strategy
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Bioenergetics in stress tolerance
appears to be confined to semelparous or semi-semelparous species (Hamel et al. 2010; Weladji et al.
2010; Fisher and Blomberg 2011). Whenever such
reversals of the priorities occur, they are by necessity
time-limited and can be incorporated into the framework of the energy-limited model of tolerance to
stress by integration of the stress-induced changes
into the aerobic scope over the organism’s life cycle.
The width and position of the stress-tolerance
window (encompassing the optimum and pejus
environmental ranges in Fig. 1) differs between different life stages and/or body sizes. Typically, early
life stages (such as developing embryos and larvae)
have elevated sensitivity to environmental stressors,
including temperature, salinity, ocean acidification,
and chemical pollutants (review by Sokolova et al.
2012). The mechanisms of high sensitivity to stress in
early developmental stages are not yet fully understood and may reflect the lower energy reserves in
young organisms and the competing demands of development versus protection from stress (Parsons
2003; Hamdoun and Epel 2007). The position and
width of the stress-tolerance window can also be
shifted by adaptation, acclimation, or acclimatization
that can improve the aerobic scope via adjustments
in mechanisms for assimilation of energy, mitochondrial abundance and capacity, enzyme activities, ion
and gas transport, and composition of membranes
(Willmer et al. 2000; Hochachka and Somero
2002). These adjustments are inevitably constrained
by the species’ physiology and environmental
conditions (such as availability of food and oxygen).
Bioenergetic markers that assess the
impacts of multiple stressors
The energy-limited concept of tolerance to stress ties
physiological changes at the cellular and organismic
levels to fitness and therefore, to ecological consequences. Although changes in the aerobic scope in
response to the environmental stressors are continuous, three important thresholds can be distinguished:
(1) a transition between the optimum and pejus
range when aerobic scope starts declining but longterm survival, growth, and reproduction are possible,
(2) a transition from pejus to pessimum range in
which aerobic scope becomes zero and only timelimited survival is possible, and (3) a transition to
the lethal range in which the aerobic scope is negative and acute mortality ensues. Bioenergetics markers associated with transitions to the pejus,
pessimum, and lethal ranges of environmental conditions can assist in predicting the ecological consequences of environmental stress including exposures
to multiple stresses (Table 1). The transition to the
pessimum range is especially important in this context, because it marks the bioenergetically unsustainable situation and determines the biogeographic
distribution of the species (Pörtner et al. 2001;
Pörtner and Knust 2007).
Aerobic scope
Measurement of aerobic scope (i.e., the proportion
of the energy and metabolic flux available for supporting fitness-related functions after the cost of the
basal maintenance is covered) provides the most
direct way of determining the transitions into the
pejus and pessimum range of environmental factors
and thus assessing the width of the stress-tolerance
window in a population. The aerobic scope sets
limits to tolerance to temperature, oxygen levels, salinity, pollution, hypercapnia, and combinations of
these stressors (Guderley and Pörtner 2010; Pörtner
2012; Sokolova et al. 2012). Recent advances in metabolic physiology and bioenergetic modeling provide
several complementary approaches that can be used
to measure aerobic scope in a variety of animals. In
active species of fish and invertebrates, aerobic scope
can be assessed by determining the difference in the
basal metabolic rate and maximum aerobic rates
during sustainable aerobic exercise (Pörtner 2002c).
Such determination requires making certain that animals are fully aerobic during the exercise and that
no functional anaerobiosis sets in, a condition that
may not be easily met in some sluggish or sedentary
species (Pörtner 2002a, 2012). In small organisms
lacking ventilatory and circulatory systems (e.g., unicellular organisms or small metazoans such as
cnidarians or flatworms), aerobic scope can be determined as the difference between maximal mitochondrial capacity and basal oxygen consumption rates.
The aerobic scope of the organism can also be
determined using approaches developed in bioenergetics-based ecological models such as the scope for
growth (SFG) and DEB family of models (Kooijman
2010; Nisbet et al. 2012). These models assess the
proportion of the assimilated energy flux invested
into different fitness-related functions (including
maintenance, production, storage, excretion, and activity), and thus, aerobic scope can be determined as
the proportion of the flux devoted to production and
activity. Both the SFG and DEB approaches have
been successfully used to model and predict growth
and reproduction of field populations of fish and
bivalves and to assess the effects of environmental
forcing variables (including pollutants, temperature,
and salinity) on these fitness-related traits
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I. M. Sokolova
Table 1 Bioenergetic markers of physiological stress and their link to fitness consequences
Environmental range
Bioenergetic markers
Degree of stress
Fitness consequences
Optimum
High-energy flux at low maintenance costs
High aerobic scope
Deposition of energy reserves (lipids, glycogen)
N/A
Maximum fitness
Pejus
High-energy flux at high maintenance costs
Reduced aerobic scope
Elevated energy costs of stress response
(e.g., stress protein synthesis)
Reduced deposition of energy reserves
Elevated expression of HSPs
Moderate
Reduced but positive fitness
functions including growth and
reproduction
Pessimum
Energy flux supports basal maintenance costs only
No aerobic scope
Metabolic rate depression
Hypoxemia
Onset of partial anaerobiosis
Suppression of protein synthesis
Increased AMPK activity
Depletion of energy reserves
Disturbances of cellular energy status
Oxidative stress
High
Limited survival but no growth or
reproduction
Lethal
Energy flux insufficient to maintain basal energetic
costs (with or without metabolic rate depression)
Negative aerobic scope
Extreme
Cellular damage
Transition to partial anaerobiosis
Disruption of cellular energy status
(including depletion of high-energy phosphates)
Oxidative stress
Disruption of integrative (e.g.,
neural) functions
Short-term survival only
Environmental ranges correspond to those shown on Fig. 1.
(Flye-Sainte-Marie et al. 2009; Baas et al. 2010;
Filgueira et al. 2011).
Whenever the aerobic scope can be determined,
this should be a preferred way to assess the stresstolerance windows; however, it may not be feasible
for all species or habitats. In these cases, it may be
possible to use a suite of indirect bioenergetic markers (such as depletion of the energy reserves, induction of the general response to stress, onset of
hypoxemia and partial anaerobiosis, disturbances of
the cellular energy status, and oxidative stress) to
infer transitions into the pejus, pessimum, or lethal
range of environmental conditions and thus determine the stress-tolerance window.
Energy reserves
Deposition of energy reserves (e.g., in the form of
carbohydrates and lipids) is a common feature of
animals that use storage to save excess energy assimilated from the environment and to buffer against
fluctuations in availability of food or demand for
energy. Deposition of the energy reserves typically
has a lower priority in allocation of energy compared
with the energetic costs of survival, reproduction,
and growth (Kooijman 2010). Thus, reduction or
cessation of the deposition of energy reserves can
be viewed as an indicator of transition into the
pejus range, while depletion of the energy reserves
may be a sign of transition into the bioenergetically
unsustainable, pessimum conditions. Depletion of
the glycogen and lipid reserves in response to environmental stressors (including temperature and salinity stress, pollutants, and their combination) is
commonly found in aquatic ectotherms and may
jeopardize their reproduction and growth, thereby
indicating cost to fitness (Allen and Downing 1986;
Encomio and Chu 2000; Smolders et al. 2004; Li
et al. 2007; Ivanina et al. 2011; Dickinson et al.
2012). The amount of glycogen or lipid reserves is
usually compared with species-specific and life-stage
specific levels found in well-fed, unstressed organisms. The reproductive state of an individual must
also be taken into account because energy reserves
are used to fuel gametogenesis and thus are affected
by the gametogenic cycle (March and Reisman 1995;
Ahn et al. 2003; Jackson et al. 2004; Mouneyrac et al.
2008; Benomar et al. 2009; Li et al. 2009).
Metabolic rate depression
Metabolic rate depression is a strategy that extends
survival in the pessimum range of environmental
conditions; it evolved in organisms from highly
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Bioenergetics in stress tolerance
variable environments such as the intertidal zone,
ephemeral bodies of water, deserts, and other habitats with extreme fluctuations of temperature,
oxygen, availability of water, and food. Metabolic
rate depression involves a strong coordinated suppression of the demand and supply of energy (and
thus a decrease in basal maintenance costs) (Guppy
and Withers 1999). This considerably extends survival time by conserving energy reserves when the
energy intake or the capacity for synthesis of ATP
are limited and can alleviate the necessity of the
compensatory onset of anaerobiosis (Guppy and
Withers 1999; Sokolova et al. 2011). However, because metabolic rate depression involves suppression
production, and consumption of ATP, there is no
net increase in aerobic scope, and the organism’s
activity decreases while its growth and reproduction
cease (Storey and Storey 1990; Sokolova et al. 2000;
Sokolova and Pörtner 2001; Marshall et al. 2011).
Therefore, an onset of metabolic rate depression
can serve as a marker of a transition into the pessimum range that incurs long-term fitness costs and is
incompatible with the indefinite survival of the population (Table 1).
Global suppression of cellular protein synthesis is
another marker associated with transition into the
pessimum environmental range and a hallmark of
metabolic rate depression (Hochachka et al. 1996;
Kwast and Hand 1996). It can be triggered by exposure to extreme hypoxia, anoxia, freezing, acute exposure to pollutants, and desiccation stress and
involves a concerted suppression of mRNA transcription, maturation, and translation processes (Kwast
and Hand 1996; Larade and Storey 2007). This
down-regulation of protein synthesis is an important
energy-saving mechanism but inevitably leads to cessation of growth and reproduction. Notably, despite
the overall reduction of the rate of transcription and
translation, specific proteins involved in protection
from stress (including molecular chaperones, antioxidants, pro-apoptotic proteins, and anti-apoptotic
proteins) may be significantly upregulated, thereby
supporting essential cellular functions during metabolic depression (Hermes-Lima et al. 1998; Larade
and Storey 2002; Teodoro and O’Farrell 2003).
Partial anaerobiosis
Onset of hypoxemia and partial anaerobiosis of tissues is considered a hallmark of transition into the
bioenergetically unsustainable pessimum range in
aquatic ectotherms and was most extensively studied
in the context of tolerance to temperature (Pörtner
2012). In aquatic ectotherms, the upper limit of
thermotolerance is set by the inability of the ventilatory and circulatory systems to deliver sufficient
oxygen to cover the tissues’ demand for energy at
high temperatures. As a result, a progressive mismatch between the oxygen consumption of tissues
and the delivery of oxygen develops at, and above,
the critical temperatures leading to tissue hypoxemia
and the onset of partial anaerobiosis, and it heralds
transition into the pessimum range. This mechanism
was shown in aquatic ectotherms, including fish,
crustaceans, polychaetes, and mollusks (Sommer
et al. 1997; Pörtner et al. 1999; van Dijk et al.
1999; Frederich and Pörtner 2000; Peck et al. 2002;
Sokolova and Pörtner 2003; Melzner et al. 2006;
Pörtner and Knust 2007; Schröer et al. 2009) but
may be less important in air–breathing ectotherms
for which high oxygen content of the air alleviates
the onset of hypoxemia (Sokolova and Pörtner 2001;
Klok et al. 2004; Stevens et al. 2010; Kutschke et al.
2013). The close relationship between thermotolerance and availability of oxygen in ectotherms is supported by the finding that hypoxia reduces the
thermotolerance, whereas elevated concentrations of
oxygen alleviate thermal stress (Mark et al. 2002;
Pörtner 2002b; Pörtner et al. 2006; Richmond et al.
2006; Le Moullac et al. 2007). Temperature and
oxygen concentration are the only two environmental variables that have been systematically studied
with regard of stress-induced hypoxemia and anaerobiosis in the pessimum range. Other stressors (such
as exposure to the trace metal Cd or to elevated CO2
concentrations) can modulate thermal tolerance by
constraining aerobic scope and shifting the upper
critical temperatures to lower values (Metzger et al.
2007; Sokolova and Lannig 2008; Lannig et al. 2010);
however, whether these and other stressors can also
induce hypoxemia and partial anaerobiosis in the
absence of thermal stress remains to be investigated.
Energetic status of cells
Indices of the energetic status of cells (such as adenylate energy charge [AEC] or ADP:ATP ratios) have
been proposed as biomarkers of stress in a variety of
organisms although their physiological implications
for cellular metabolism are debated (Isani et al.
1997; Thebault et al. 2000; Hardie and Hawley
2001). Studies in the context of the OCLTT and
energy-limited tolerance of stress indicate that cellular energy status (including concentrations of adenylates, AEC, ADP/ATP ratios, and Gibbs’ free energy
of ATP hydrolysis) is tightly regulated so that significant shifts in these parameters are only observed
during exposure to severe stress (typically in the
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pessimum and lethal ranges) (Sokolova et al. 2000,
2005; Melzner et al. 2006; Morley et al. 2009a;
Ivanina et al. 2010, 2011; Dickinson et al. 2012).
Oxidative stress
Stress-induced metabolic disturbance can result in
oxidative stress due to the increased generation of
reactive oxygen species or nitrogen species and/or
suppression of the antioxidant defenses. Oxidative
stress can be induced by a variety of environmental
factors including temperature, hypoxia, and pollutants (Kelly et al. 1998; Livingstone 2001; Abele and
Puntarulo 2004). During exposures to moderate
stress in the pejus range, antioxidants and other
mechanisms of cellular protection are overexpressed,
thereby maintaining the redox balance, so that oxidative stress is either not observed or occurs transiently (Abele and Puntarulo 2004; Storey and Wu
2013). The onset of oxidative stress is typically associated with severe stress and with a transition into
the pessimum range of environmental conditions
(Abele and Puntarulo 2004; Kurochkin et al. 2009;
Sokolova et al. 2011; Storey and Wu 2013). It is
worth noting that interpretation of the markers of
oxidative stress may be complicated due to high species-specific variability and the effects of diet and
physiological status (Hõrak and Cohen 2010),
thereby making them less dependable as markers of
the pessimum range.
Other potential markers
Molecular chaperones (such as heat-shock proteins
[HSPs]) have been proposed to mark transition
into the pejus range (Pörtner 2012). HSPs are constitutively expressed in the cell where they facilitate
correct folding of proteins and stabilize proteins and
membranes and are induced by a broad variety of
stressors including extreme temperatures, exposure
to pollutants and toxins, salinity stress, UV light,
and hypoxia (Nagao et al. 1990; Sanders 1993).
Synthesis and the chaperoning action of HSPs are
ATP-demanding, and HSPs account for up to 10%
of the total proteins under control conditions, and
for an even larger fraction during stress (Kueltz
2003). Thus, elevated expression of HSPs poses a
considerable energetic expense and is associated
with reduced aerobic scope and fitness costs in the
pejus range (Hoffmann and Somero 1995; Anestis
et al. 2007; Petes et al. 2008). However, although
the onset of HSP response occurs during the transition into the pejus range, elevated expression of
HSPs also are often maintained in the pessimum
and lethal ranges; this caveat must be taken into
I. M. Sokolova
account when using HSP expression as a bioenergetic
marker for the pejus range of environmental
conditions.
Recent studies also indicate that protein kinases
involved in sensing of cellular energy and in signaling of stress may serve as potential markers of
transitions from the optimum to energy-stressed
and energy-deficient (non-sustainable) states. Thus,
AMP-activated protein kinase (AMPK) was shown
to be a sensitive indicator of transition into the
pejus range during heat stress in crustaceans
(Frederich et al. 2009). Cyclic AMP-activated protein
kinase (protein kinase A [PKA]) is a marker associated with transition to metabolic arrest (and thus in
the pessimum range) in many species; however, response to PKA is species-dependent, and PKA is activated during metabolic arrest in some species and
suppressed in others (MacDonald and Storey 1999;
Ramnanan et al. 2010). Given an important role of
reversible protein phosphorylation in coordination of
cellular metabolism, protein kinases are likely to play
a key role in stress-induced metabolic shifts and
future studies should reveal their full potential as
markers of ecologically-relevant physiological
transitions.
Conclusions and perspectives
The concept of energy-limited tolerance to stress
provides a useful tool for assessing the effects of
multiple stressors under environmentally realistic
scenarios in aquatic ectotherms and potentially in
other organisms. This approach focuses on the bioenergetic consequences of exposures to stress that
arise from the inevitable trade-offs between allocation of energy to survival, stress-tolerance, and
other fitness-related functions. It uses energy balance
as a common denominator to determine the combined effects of multiple stressors and their consequences for fitness. This makes this approach
applicable to a wide variety of environmental variables that have direct or indirect impacts on energy
metabolism. Bioenergetic markers proposed in this
review can be used to assess ecologically important
transitions into the pejus range (where the long-term
survival of the population is possible at the cost of
reduced production) and the pessimum range (which
coincides with the tolerance limits of the population
and defines the distributional range of the species in
the face of multiple stressors). These markers will
certainly be complemented and refined as more studies on the metabolic effects of environmental stressors become available. A potentially fruitful avenue
for such studies that has not been fully explored in
Bioenergetics in stress tolerance
aquatic ectotherms is the study of cellular signaling
cascades involved in metabolic regulation and
response to stress. Bioenergetic framework may also
be useful for understanding the relationships between
aging, longevity, and tolerance to stress, which may
be directly linked to aerobic scope in energy-limited
natural populations (Parsons 2003, 2007). Direct
effects of bioenergetic shifts on fitness provide a suitable framework for fusing physiology, functional
ecology, and evolutionary biology and to improve
our understanding of the driving forces and the constraints of environmental adaptations (including but
not limited to, scenarios of exposures to multiple
stresses common in nature). Focus on the bioenergetic sustainability of populations also can assist in
assessment of ecological risk and of conservation
practices by identifying the habitats that are capable
of supporting viable populations of ecologically or
economically important, or otherwise protected,
species.
Acknowledgments
I thank Anne Todgham and Jonathon Stillman for an
invitation to present this work at a special symposium (2013 Annual Meeting of the Society for
Integrative and Comparative Biology) that provided
fruitful discussions for this manuscript. The Society
for Integrative and Comparative Biology and the
National Science Foundation sponsored this symposium and funded my participation.
Funding
Supported by the National Science Foundation
(IOS-0951079 and IBN-0347238).
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