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11-1-2004

Exergy use in bioenergetics

Yasar Demirel
Virginia Polytechnic Institute and State University, [email protected]

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Demirel, Yasar, "Exergy use in bioenergetics" (2004). Papers in Analytical Chemistry. 4.

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 Exergy use in bioenergetics

Abstract
Every developed and adapted biological system extracts useful energy from outside,
converts, stores it, and uses for muscular contraction, substrate transport, protein synthesis,
and other energy utilizing processes. This energy management in a living cell is called the
bioenergetics, and the useful energy is the exergy, which is destroyed in every irreversible
process because of the entropy production. The converted exergy is the adenosine
triphosphate (ATP) produced through the oxidative phosphorylation coupled to respiration
in which the exergy originates from oxidation of reducing equivalents of nutrients. A living
cell uses the ATP for all the energy demanding activities; it has to maintain nonvanishing
thermodynamic forces, such as electrochemical potential gradient, and hence is an open,
nonequilibrium system, which manages the exergy destruction and power production to
adapt the fluctuations in energy demand and production within mitochondria. A simplified
example presented here shows that the use of exergy analysis is helpful for understanding
and analysing oxidative phosphorylation in bioenergetics.

Keywords: degree of coupling; dissipation; exergy; nonequilibrium thermodynamics;

oxidative phosphorylation.

Comments: This paper originally was published in The Journal of “Int. J. Exergy”, Vol.1,
No.1, 2004 and Copyright © 2004 Inderscience Enterprises Ltd.
 Introduction
Exergy is mainly associated with the energy interactions between a physical process and the environment.
As a process progress towards equilibrium with the environment, we explore the ways of extracting the
maximum useful shaft work or electrical work. This naturally implies the exergy-aided cost optimization
based on the combination of the thermodynamic optimum and the principles of economic engineering.
However, the implications of exergy use in biological systems are addressed inadequately, although a
living cell is an open system with continuous energy and matter interactions with the environment, and
operating away from equilibrium as an organized and dissipative structure.

Mitochondria in a living cell contain the inner and outer membranes made of bilayers, which may
influence the coupling and local gradients of ions, molecules, and macromolecules in the regulation of
energy metabolism (Mannella, 2000). Structural anisotropy in the mitochondria is necessary for a
chemical reaction to be coupled with a substrate flow process in a cell according to the Curie-Prigogine
principle (Demirel and Sandler, 2002). The inner membrane houses the respiratory chain and ATP
synthesis in oxidative phosphorylation (OP). The energy source for the phosphorylation is the oxidation
of reducing equivalents of nutrients via the respiratory chain. Mitochondria have various complexes for
converting substrate into energy (Lemasters, 1984). These complexes pump protons (H+) from the matrix
into the intermembrane space (Kadenbach et al., 2000). This forms an electrochemical proton gradient
across the inner mitochondrial membrane. The ATP synthase uses this electrochemical potential gradient
for the synthesis of ATP from adenosine diphosphate (ADP) and phosphate (Pi), which drives the
majority of energy utilizing processes in the cell. The energy metabolism in the cell has to optimize the
rate of energy production and constantly changing energy demand, such as increasing thermogenesis at
low temperatures, preparing appropriate responses under stress conditions, and efficient use of nutrients.
TIus optimization incorporates several control mechanisms including a slip of proton pumps and proton
leak across the bilayer (Kadenbach et al., 2000). However mitochondria cannot maximize the ATP
production and exergetic efficiency at the same time (Cairns et al., 1998). This study presents the
exergetic aspects in bioenergetics using a simplified example of OP.

Nonequilibrium thermodynamics

In a nonequilibrium system some of the intensive parameters are functions of time and position and a
local thermodynamic equilibrium state exists in small volume elements at each point. These volume
elements contain enough molecules to be treated as homogeneous, and the thermodynamic properties
may be determined at every point in the same way as for substances in equilibrium. The postulate of
local thermodynamic equilibrium is valid if the gradients of intensive thermodynamic functions are
small, and their local values vary slowly in comparison with the relaxation time of the local state of the
system (Cairns et al., 1998; Demirel, 2002; Katchalsky and Curran, 1967; Kondepudi and Prigogine,
1999). The local thermodynamic equilibrium implies the microscopic reversibility that is the probability
of a microscopic process occurring in one direction of time is the same as that in the reverse direction
(Kondepudi and Prigogine, 1999). For a simple reversible reaction, the principle of microscopic
reversibility means that if one of the paths is preferred for the forward reaction, the same path must also
be preferred for the reverse reaction (Levenspiel, 1999):
Using the local thermodynamic equilibrium approach, nonequilibrium thermodynamics calculates the
rate of entropy production (diS/dt) or the dissipation ψ due to irreversible processes in a system. The
dissipation function ψ is derived from the entropy balance beside the general balance equations of mass,
momentum, energy, and the Gibbs relation, and expressed by
 where Jk is the flow, or output, such as energy flow, or rate of reaction, and Xk is the thermodynamic
force that causes a flow, such as chemical potential gradient or chemical affinity A, Aj, = -ΣAjvij,where
vij is the stoichiometric coefficients of reaction j. Equation (1) identifies the conjugate flows and forces
to be used in the phenomenological equations, which relate the forces and flows linearly through the
phenomenological coefficients L ij

In Equation (2), the cross coefficients L ij (i #j) are symmetric according to the Onsager reciprocal
relations, and relate the coupled flows. Coupling implies an interrelation between flow i and flow j so
that, for example, a substance can flow without or against its conjugate driving force (Caplan and
Essig, 1983; Demirel, 2002; Howland and Needleman, 2000; Jencks, 1989; Stucki et al., 1983;)
without violating the second law of thermodynamics.

Energy conversion
Experiments and empirical analysis of different cellular process show that linear relations exist
between the rate of respiration and growth of many microbial systems with mechanisms to optimize
the exergetic efficiency for some of the individual processes of OP (Lemasters, 1984; Mannella, 2000;
Rigoulet et al., 1998; Rottenberg, 1979; Santillan et al., 1997; Soboll and Stucki, 1985; Stucki, 1980a,
1984, 1991; Stucki et al., 1983). This might be the result of a special kinetics of enzyme reaction, such
as the Michaelis-Menten equation, which shows that the enzyme reactions in certain regions can be
approximated as linear (Levenspiel, 1999). Existence of a multiple inflection point in the force-flow
space of a system of enzyme-mediated reactions suggests that a steady state in the vicinity of the linear
region occurs over a considerable range, and linear relations may be favored for a highly coupled
energy transducer, since local asymptotic stability is guaranteed, although the system may be far from
equilibrium (Baumann, 1991; Caplan and Essig, 1983; Natl~, 1998; Nielsen, 1997; Pfeiffer et al.,
2001; Rothschild et al., 1980; Rottenberg, 1979; Stucki, 1980a, 1984; Walz and Caplan, 1995;
Westerhoff, 1982). Intrinsic linearity would have an energetic advantage as a consequence of evolution
(Heinrich and Schuster, 1998; Rothschild et al., 1980; Stucki et al., 1983). Stucki (1980a)
demonstrated that variation of the phosphate potential at constant oxidation potential yields linear
flow-force relationships in the mitochondria. Extensive ranges of linearity are also reported for the
reaction driving the active sodium transport in epithelial membranes, where the sodium transport
occurs close to a stationary state (Candia and Reinach, 1982; Lagarde, 1976; Stucki et al., 1983) where
the entropy production or the destruction of exergy reaches a minimum value. Cells optimize their free
energy production and utilization by lowering their entropy production and hence exergy destruction
(Toussaint and Schneider, 1998).

The second law of thermodynamics states that entropy production or exergy destruction as a
consequence of the irreversibility is always positive. In mitochondria, a representative overall dissipation
function or the exergy destruction for OP may be obtained from Equation (I), and expressed by (Caplan
and Essig, 1983; Demirel, 2002; Katchalsky and Curran, 1967; Stucki, 1980a).
where the input force X0 is the redox potential of oxidisable substrates, and Xp is the output force
representing the affinity A, or the phosphate potential expressed by Xp = (ΔGp0+RT
ln([ATP]/([ADP][Pi])), where ΔGp0 is the Gibbs free energy at standard conditions. The associated input
flow Jo is 'the net oxygen consumption, and the outflow Jp is the net rate of ATP production. For the sum
to be positive in Equation (3), we can have either Jo Xo > 0, Jp Xp > 0, or Jp Xp < 0, while the other is
positive and large enough to compensate the negative effect of the first term. If the system is an energy
converter, we have the ATP production Jp Xp (driven process), coupled to the respiration Jo Xo (driving
process) (Bisch, 1993; Caplan and Essig, 1983; Krupka, 1998; Prigogine, 1967; Rottenberg, 1979;
Rottengberg and Gutman, 1977; Waldeck et al., 1998; Walz, 1979). In the uncoupled respiration no
gradients are formed, and the respiration is not controlled by the energy consumption in the cell. This
may be the result of a modified energy-coupled respiratory chain (Skulachev, 1998). This sequence of
coupling is controlled at switch points where the mobility, specificity and catalysis of the coupling
protein can be altered is specific ways such as sifted equilibria or regulated rates of conversion between
one protein state and another (Krupka, 1998). Prigogine (1967) showed that the total exergy destruction
reaches a minimum in a stationary state, which is the stability criterion of a stationary state (Kondepudi
and Prigogine, 1999). Optimal performance regimes of biological systems are associated with minimum
entropy production.
The exergetic efficiency 77 is defined as the ratio of dissipations due to output and input powers in
OP, and from Equation (3) we have

It is customary to use the following simplified, representative linear phenomenological equations for the
overall OP (Cairns et a], 1998; Stucki, 1980a)

The matrix of the phenomenological coefficients must be positive definite; for example, for a two-flow
system we have Lo > 0, Lp > 0 and Lo Lp –Lop Lpo> 0. The cross-phenomenological coefficient Lop
represents the mechanism of coupling of this complex coupled process. Lo shows the influence of
substrate availability on oxygen consumption (flow), Lp is the feedback of the phosphate potential on
ATP production (flow). The cross-coupling coefficient Lop shows the phosphate influence on oxygen
flow, while Lpo shows the substrate dependency of ATP production. Experiments show that Onsager's
reciprocal relations holds for OP, and we have Lop = Lpo, (Caplan and Essig, 1983; Stucki, 1980a).
Equations (5) and (6) are valid only in the vicinity of the equilibrium state (Stucki, 1980a; Stucki et al.,
1983). Such linear energy converters are characterized by an optimal efficiency ηopt,(Caplan and Essig,
1983; Stucki, 1980a)
where q is called the degree of coupling that is expressed in terms of the phenomenological coefficients
Lij (Kedem and Caplan, 1965)

Here q is a lump-sum degree of coupling for the various individual degrees of coupling of different
processes of OP driven by the respiration. Absolute values of degree of coupling vary from zero for
completely uncoupled systems to unity for completely coupled systems O< |q| < I.
By dividing Equation (5) by Equation (6), and by further dividing the numerator and denominator by
Xo (Lo Lp)1/2, we obtain

where

Equation (9) shows the exergetic efficiency η in terms of the force ratio x and the degree of coupling q.
The term Z is called the phenomenological stoichiometry (Caplan and Essig, 1983). The ratio Jp/Jo is the
conventional phosphate to oxygen consumption ratio.

Exergy destroyed
For the OP described by Equations (5) and (6), the exergy destroyed can be obtained from Equation (3)
in terms of the force ratio x and the degree of coupling q, and given by

Minimum exergy destruction or the minimum entropy production at the stationary state provides a
general evolution criterion as well as a stability criterion (Cairns et al., 1998; Glansdorff and Prigogine,
197 1; Kondepudi alld Prigogine, 1999; Nicolis and Prigogine, 1977; Toussaint and Schneider, 1998).
Entropy production rate decreases as |q| increases, reaching an optimum value at which |q| = 1
corresponding to the steady state at equilibrium.

There are two important steady states identified in the cell: (i) static head (sh), and (ii) level flow (If). At
static head, where the ATP production is zero Jp =0, the Coupling between the respiratory chain and OP
emphasizes to maintain a phosphate Potential Xp, which can be obtained from Equation (5) as (Xp)sh= -
qXo/Z, and the Static head force ratio xsh becomes xsh = -q. The oxygen flow Jo at static head is obtained
from Equations (5) and (6)
Where Lo may be interpreted as the phenomenological conductance coefficient of the respiratory chain.
If an uncoupling agent, such as dinitrophenol (Cairns et al., 1998), is used the ATP production vanishes
and hence Xp =0, then Equation (5) becomes

Combining Equations (11) and (12), we obtain

Using the experimentally attainable static head condition (state 4 in mitochondria) and the uncoupled
oxygen flow (Jo)unc we can determine the degree of coupling q.

At constant Xo Equation (10) yields the minimum value of exergy destroyed at x= -q

The ratio of dissipations expressed in Equations (15) and (10) depends only on the force ratio and the
degree of coupling, and becomes an exergy distribution ratio over the values of x.

At level flow, the phosphate potential vanishes, and no net work is performed by the mitochondria, and
the flow ratio becomes

The combination of Equations (16) and (17) yields an expression for estimating the phenomenological
stoichiometry Z from measured Jp/Jo=P/O ratios at level flow

The efficiency expressed in Equation (9) is zero at both static head and level flow, due to vanishing
power at these states. Between the static head and level flow efficiency passes through an optimum,
which is given in Equation (7).
The force ratio at optimal efficiency is expressed by (Stucki, 1980a)
The rate of optimal efficiency of OP is not characterized by the exergy decrease (Stucki, 1980a), and the
exergy destroyed at optimal efficiency is given by

Ratio of dissipations ψopt and ψ, given in Equations (20) and (10) respectively, shows the effect of
optimal operation on the exergy destruction in terms of the force ratio and the degree of coupling only

For the optimal efficiency to occur at steady state, OP progress with a load causing certain dissipation.
Such a load JL is an ATP utilizing process in the cell, such as the transport of substances. A load, which
will make the steady state as the optimal efficiency state, can be identified through the total exergy
destroyed ψc

Here JL is the net rate of ATP consumed and X is the driving force. If we assume that ATP-utilizing
process is driven by the phosphate potential Xp and the JL is linearly related to Xp then we have JL = LXp
.Here L is a phenomenological conductance coefficient. The dissipation caused by the load is JL Xp =

L Xp 2and the total exergy destroyed is expressed by

Using Equation (19), and from the extremum of Equation (23), Stucki (1980a) found the condition

and called the conductance matching of OP. Here,β shows the percentage of the conductance matching.
After combining Equations (23) and (24), we obtain

The exergies destroyed at static head with conductance matching (ψc)h and at the state of optimal
efficiency (ψc)opt are expressed by Stucki (1980a) as follows
It is now possible to estimate the ratios of exergies ø3and ø4 in terms of the force ratio x and the degree
of coupling q by using Equations (25)-(27)

Equations (28) and (29) are analogous to those Equations (16) and (21) and show the ratios of exergy
destructions with and without the load.
Linear OP is interpreted as a result of some type of optimization that the efficiency of various
biological converters at far from equilibrium is greatly improved by linear relations between flows and
forces (Stucki et al., 1983). Comparisoll of energy conversions in linear and nonlinear regions requires
a combination of thermodynamic and kinetic considerations to express the exergetic efficiencies of
nonlinear ηnland linear ηl modes

Donating γ as a measure for the relative binding affinity of a substrate (H+) on the
either side of the membrane, the following inequalities are obtained for γ ≥1 (Stucki
et al., 1983)

where ζ is the reduced stoichiometry (Z/n),which is subjected to kinetic limitation (1/q) ≥ ζ≥q, and n is
the mechanistic stoichiometry. Inequalities (31) and (32) suggest that at a certain value of ζ the
efficiencies of nonlinear and linear modes become equal to each other. This means that there exist
values for ζ where the energy converter operates more efficiently. A fully coupled system is
incompatible with optimal efficiency in biological energy converters operating at nonvanishing output
flows. A ratio of efficiencies at linear and nonlinear modes

is a measure for the efficiency gain in linear mode operation. The efficiency in linear mode depends on
only q (Equation (7)), while the efficiency nonlinear mode depends on input force X, beside q. In the
nonlinear region, the efficiency decreases at high values of input force, and the force ratio at optimum
operation xopt, nl is shifted towards level flow where x =0 (Stucki et al., 1983). I11 OP the input force is
the redox potential of the oxidisable substrates and the output force is the phosphate potential. If these
two forces are balanced, the system operates close to reversible equilibrium. This means that the system
would be completely coupled, and two processes would merge into a single process governed by a single
force. Experiments show that in mitochondria y < 1, and input force is well above 50RT (Caplan and
Essig, 1983;Lemasters, 1984; Stucki, 198Oa). For a fully coupled system in nonlinear region of a single
force, the phosphate potential Xp would be very small. However, a dissipative structure can only be
maintained with a considerable Xp. On the other hand, in the linear mode of operation, optimum force
ratio xopt does not depend on input force (Equation (19)) (Soboll and Stucki, 1985; Stucki, 1980a; Stucki
et al., 1983).

The gain ratio ηr can be calculated at a reference force ratio, such as xopt, which is a natural steady-state
force ratio of OP in the liver cell (Stucki et al., 1983). This is seen as the result of adaptation of OP to
various metabolic conditions and also results from thermodynamic buffering of reactions catalyzed by
enzymes (Stucki, 1980b). Experimentally observed linearity of the several energy converters operating
far from equilibrium is due to enzymatic feedback regulation with an evolutionary drive towards higher
efficiency (Howland and Needleman, 2000; Stucki, 1980b, 1984). W11en the conductance matching is
fulfilled, energy conversion could be accomplished without any losses if |q| = 1, corresponding to
maximal power output. However, |q| = 1 implies that load conductance coefficient L in Equation (24)
vanishes, which is of no interest for a living organism, since the absence of a load leads to equilibrium
representing the dead state. Therefore a living organism requires |q| < 1. The particular value of degree of
coupling depends on the nature of the output required from the energy converter. Stucki (1980a, b)
outlined various output modes:

• For a maximal net rate of ATP flow at optimal efficiency (Jp)opt the degree of coupling is
estimated as qf = 0.786

• For an economic net ATP flow (JPη)opt we have qfec-= 0.953

• For a maximal output power (Jp Xp)opt at optimal efficiency, qp =0.91

• For an economic net output power (Jp Xpη)opt,we have qpec = 0.972.

These experimental results show that the degree of coupling is not a constant but a variable subject to
metabolic requirements and physiological organ roles (Cairns et al., 1998; Soboll and Stucki, 1985;
Stucki, 1980a). For example, fatty acids decrease the degree of coupling, and function as uncouples.
Uncoupling is not restricted to thermoregulation; some uncoupling activity is favorable for the
performance of the metabolic and even the energy-conserving functions of cellular respiration (Shlachev,
1998; Stucki et al., 1984). Mitochondria could regulate the degrees of coupling of OP depending on the
energy demand of the cell. For example OP of the fed rats operates very close to conductance matching,
i.e. at the state of optimal efficiency at the economic degree of coupling (Cairns et al., 1998; Stucki,
1980a, b).

Figure 1 shows the change of efficiencies η, given in Equation (9), in terms of flow ratio x between -1
and 0, and for the particular degrees of coupling qf, qp, qf ec and qpec. As Equation (7) shows, the optimum
efficiency values are only dependent on the degrees of coupling, and increase with increasing values of
q. The values of efficiency reach maximums changing between 0.2359 and 0.6195 corresponding to qf
and qpec, respectively.
Figure 1 The change of efficiencies η, given in Equation (9), in terms of flow ratio x and for
the degrees of coupling qf, qp, qf ec and qpec.

Figures 2-5 show the ratios of exergy destructions for unloaded and loaded OP in terms of x and the four
degrees of coupling qf, qp, qf ec and qpec. These ratios change between x = -1 and =0 exhibiting a
maximum value at a certain flow ratio x. Figure 2 shows that the values of ø1 reach unity at
various values of x, and the economic degrees of coupling qf ec, and qpec yield lower values of ø1,
compared with those obtained for qf, qp. Exergy destructions at static head are relatively lower at
the degrees of coupling corresponding to economical ATP production and power output. Figure
3 shows that the values of d ø 2, expressed in Equation (21) with xopt = -√ηopt, reach some peak
values higher than unity, and clearly shows that exergy destruction is not minimized at optimal
efficiency of OP. The exergy destruction is the lowest at the degree of coupling corresponding to
the economical power output.
 Figure 4 shows the change of ø3expressed in Equation (28), when a load is attached with the values β =
1 and β = 0.9 at static head. With the load, the exergy destruction increases considerably. This increase is
relatively larger with decreasing values of β. Figure 5 shows the values of ø 4, expressed in Equation (29),
with β = 1 and β = 0.9. At optimal efficiency, exergy destruction is the lowest at gf> qf corresponding to
the maximum production of ATP, while the exergy destruction is relatively higher at economic power
output with a minimal effect of β.
The load in a living cell fluctuates and compromises optimal efficiency of OP. Some enzymes operate
as sensitive thermodynamic buffering to decrease deviations from optimal efficiency (Korzeniewski,
1997; Soboll, 1995; Soboll and Stucki, 1985; Stucki, 1980b; Stucki et al., 1984; Veuthey and Stucki,
1987; Westerhoff, 1993; Woitczak and Schonfeld, 1993). One intrinsic uncoupling is called the slippage,
and results if one of the two coupled reactions of a cyclic process proceeds without its counterpart
(Tomashek and Brusilow, 2000); for example an enzyme passes a proton without ATP synthesis, or
utilizes ATP without pumping the proton. Although slippage decreases the exergetic efficiency, it enables
an enzyme to control and regulate ever changing forces and demands (Tomashek and Brusilow, 2000).
ATP utilizing reactions may be irreversible ones, which act as load, while reversible ones act as
thermodynamic buffers. This regulatory mechanism allows OP to operate with an optimal use of the
exergy contained in the nutrients. Every reversible ATP utilizing reaction can, in principle, act as a
thermodynamic buffer. For example adenylate kinase can buffer the phosphate potential X, to the value
permitting optimal efficiency of OP in the presence of too high loads (Stucki, 1980b; Stucki et al., 1984;
Veuthey and Stucki, 1987). The adenylate kinase reaction is reversible, and acts as a buffer (Stucki,
1980b). If this buffer is treated as another load with a conductance Lo, the overall load conductance L*
becomes

where

Stucki (1980b) expressed the dissipation function with buffering from Equation (23) in terms of L*

Dividing Equation (35) with Equation (23) shows file effect of thermodynamic buffering on the exergy
destruction
Figure 6 shows the change of ø5 in terms of x between 0 and -1 for the degrees of coupling qf, qp, qf ec and
qpec with the load conductance of L = 0.5 and L =0.9. The values of ø5 are lowest at economical power
output and highest at maximum output of ATP. Therefore the exergy destruction is relatively lower in
economical power output than that of maximum ATP flow.

Within the framework of the theory of the dissipative structures (Kondepudi and Prigogine, 1999;
Prigogine, 1967), the thermodynamic buffering (Stucki, 1980b) represents a new bioenergetics regulatory
principle for the maintenance of a far from equilibrium regime. Due to the ATP production in OP, the
phosphate potential is shifted far from equilibrium. Since ATP drives many processes in the cell, the shift
in Xp to far from equilibrium results a shift of all the other potentials into far from equilibrium regime.
Conclusions

Using the nonequilibrium thermodynamic analysis, we can express the exergetic efficiency, the rate of
entropy production and the exergy destroyed in terms of the degree of coupling in bioenergetics. The
simplified analysis presented shows that the higher exergetic efficiency may not always imply an
economical operation in oxidative phosphorylation. In bioenergetics, maximum energy production and
optimum operation are adjusted and optimized for fluctuations in demands of energy production and
consumption through various degrees of coupling. Like in a physical system, the exergy analysis in
bioenergetics helps to describe complex-coupled phenomena.