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Circulation Research
NOVEMBER
VOL. 37
1975
NO. 5
An Official Journal of the American Heart Association
Brief Reviews
The Metabolic Significance of the Malate-Aspartate
Cycle in Heart
By Brian Safer
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• Under physiological conditions, the energy
requirements of the heart are met primarily by the
oxidation of fatty acids, glucose, and lactate (1, 2).
Initially, during the metabolism of glucose and
lactate, the coenzyme NAD is reduced to NADH
and pyruvate is formed in the cytosolic compartment 1 of the myocardial cell. Subsequent entry of
pyruvate into the mitochondria for oxidative metabolism in the citric acid cycle requires an equivalent oxidation of cytosolic NADH by the mitochondrial electron transport chain, which regenerates
NAD. However, direct transfer of the reduced coenzyme NADH to the respiratory chain is prevented by a selective permeability barrier across
the inner mitochondrial membrane to NADH as
well as other metabolic intermediates (3, 4). Although several indirect shuttle mechanisms have
been proposed (5-7), current evidence indicates
that the reducing equivalents formed in the reduction of cytosolic NAD to NADH are indirectly
carried into the mitochondrial compartment of the
heart and other tissues by metabolic anions of the
malate-aspartate cycle (8-11). In addition, interaction of the malate-aspartate cycle with the citric
acid cycle, through key common metabolic intermediates, may provide a major mechanism by
which coordination of mitochondrial and cytosolic
energy metabolism is achieved in the myocardium
(9, 12, 13).
OXIDATION OF CYTOSOLIC NADH BY THE MALATE-ASPARTATE
CYCLE
In the malate-aspartate cycle, cytosolic NADH
generated at either glyceraldehyde-3-phosphate
From the Molecular Hematology Branch, National Heart and
Lung Institute, National Institutes of Health, Bethesda, Maryland 20014.
'The term cytosolic compartment designates the intracellular space exclusive of the water-permeable space enclosed by the
inner mitochondrial membrane.
Circulation Research, Vol. 37, November 1975
dehydrogenase or lactate dehydrogenase is oxidized
back to NAD by the reduction of oxaloacetate to
malate (Fig. 1). Malate then crosses the inner
mitochondrial membrane to enter the mitochondrial matrix where oxidation of malate regenerates
oxaloacetate and NADH. In this manner, cytosolic
reducing equivalents from NADH are indirectly
transferred via malate to the respiratory chain for
oxidation.
The return of oxaloacetate thus formed in the
mitochondrial compartment to the cytosolic compartment, which completes the malate-aspartate
cycle, appears to be limited by a selective impermeability of the inner mitochondrial membrane and
the low intramitochondrial concentration of oxaloacetate. Instead, oxaloacetate is transaminated
with glutamate in the mitochondrial compartment
to form a-ketoglutarate and aspartate. Aspartate
and a-ketoglutarate are able to cross the inner
mitochondrial membrane, and, by the reverse
transamination, oxaloacetate and glutamate are
regenerated in the cytosolic compartment to complete the cycle (5, 6, 14). Distinct cytosolic and
mitochondrial isoenzymes of malate dehydrogenase
and aspartate aminotransferase catalyze these reactions (15).
ROLE OF METABOLIC ANION EXCHANGE CARRIERS IN THE
MALATE-ASPARTATE CYCLE
Indirect calculations based on levels of oxidized
and reduced metabolites in several tissues (16-18)
suggest that, in the heart, the mitochondrial pyridine nucleotide pool is also maintained at a level
considerably more reduced than that of the cytosol
(the ratio of NADH to NAD is 10-100-fold higher in
the mitochondria). Therefore, transfer of cytosolic
reducing equivalents to the respiratory chain is
energetically unfavorable and cannot occur by free
diffusion of the metabolic anions of the malate527
528
SAFEF
CYTOSOL
GLU
-,
NAD
— -MAL
a-KG
TRIOSEP
\
GLU
ASP
ASP —
II
GLUCOSE
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INNER
MITOCHONDRIAL
MEMBRANE
MATRIX
FIGURE 1
The malate-aspartate cycle. NADH formed in the cytosolic compartment of the cell is oxidized by the
reduction of oxaloacetate (OAA) to malate (MAL). Malate then indirectly transfers these reducing
equivalents into the mitochondrial compartment where oxaloacetate and NADH are regenerated. For
steady-state operation of the malate-aspartate cycle, oxaloacetate must be continuously returned to
the cytosolic compartment. Because of its low concentration in the mitochondria and the relative
impermeability of the mitochondrial membrane to oxaloacetate, this transfer is also indirectly
accomplished by transamination with glutamate (GLU) to form a-ketoglutarate (a-KG) and
aspartate (ASP). These substances are then transferred to the cytosolic compartment where the
reverse transamination regenerates oxaloacetate and glutamate. Distinct mitochondrial and cytosolic
isoenzymes catalyze these reactions. A specific electroneutral carrier system catalyzes the equal and
opposite exchange of malate and a-ketoglutarate (I). The aspartate-glutamate antiport system (II),
in contrast, appears to be electrogenic. By directly utilizing the free energy of the electrochemical
gradient established by electron transport, cytosolic NADH can be indirectly transferred into the
mitochondrial compartment against a NADH-NAD potential gradient. LAC = lactate, PYR =
pyruvate, and TRIOSE-P = glyceraldehyde-3-P and a-glycerophosphate.
aspartate cycle across the inner mitochondrial
membrane. It has been demonstrated, however,
that such anion exchange is mediated by specific
carriers,2 some of which may be energy linked (14,
19-21). In coupled mitochondria, transfer of electrons in the respiratory chain results in the production of a small pH gradient (< 0.5 pH units,
alkaline inside) and an electrical potential gradient
(< 250 mv, negative inside) across the inner
membrane. Recent evidence suggests that the
2
Mitochondrial anion translocators are classified as either
antiport systems which exchange ions or symport systems which
promote unidirectional coupled transfer of ions across the inner
mitochondrial membrane. Electroneutral carriers do not alter
charge separation across this membrane, but electrogenic carriers can directly utilize the electrochemical potential gradient
established by electron transport to energize transport of
metabolic anions (14-16).
anion exchange carriers can directly utilize thes
potential gradients to drive the malate-aspartai
cycle (19, 22-26).
During the steady-state operation of the malatt
aspartate cycle, malate is exchanged stoichiometr
cally for a-ketoglutarate across the inner mitochor
drial membrane by a specific electroneutral ant
port system (27) according to the net chemici
gradient. It had been proposed that this malate-c
ketoglutarate exchange carrier (labeled I in Fig. '.
is driven by the pH gradient across the inn*
mitochondrial membrane (19). However, althoug
this mechanism is feasible in the liver, it cannot t
the primary energy source for the malate-aspartai
cycle in the myocardium, since the activity of tr
malate-phosphate exchange carrier (also require
for utilization of the pH gradient) is low in hea
Circulation Research, Vol. 37, November 19
MALATE-ASPARTATE CYCLE
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mitochondria (21, 22, 27, 28). In addition, the pH
gradient (alkaline inside) established by electron
transport opposes transport of malate and a-ketoglutarate in the direction required for removal of
cytosolic reducing equivalents.
The primary energy source for the malate-aspartate cycle appears to be the aspartate-glutamate
antiport system. In contrast to the electroneutral
malate-a-ketoglutarate antiport system, exchange
of glutamate and aspartate appears to be electrogenie due to the carrier-mediated cotransport of
one proton per glutamate molecule. Thus, a net
transfer of charge accompanies this exchange,
which permits direct utilization by the aspartateglutamate exchange carrier (labeled II in Fig. 1) of
the potential gradient established by the outwarddirected proton pump that is coupled to electron
transport (24-26). Expenditure of energy to maintain the electrochemical gradient across the inner
mitochondrial membrane during electron transfer
may therefore provide the energy required for
uphill transfer of reducing equivalents by the
malate-aspartate cycle against an NADH-NAD
potential gradient (29). In addition, since this
carrier can only exchange intramitochondrial aspartate for extramitochondrial glutamate (24-26,
30, 31), transfer of reducing equivalents is permitted only from the cytosolic to the mitochondrial
compartment.
INTERACTION OF THE MALATE-ASPARTATE AND CITRIC ACID
CYCLES AND NONUNIFORM CITRIC ACID CYCLE FLUX
Through shared metabolic intermediates, the
malate-aspartate cycle interacts directly with the
citric acid cycle in the region of citrate synthetase
and a-ketoglutarate dehydrogenase. As a result,
the flux of substrates through different portions of
the citric acid cycle may not be equal but is
modulated by the relative rates of reaction at two
metabolic branch points indicated by the asterisks
in Figure 2 (12, 13). The two key enzymes which
determine the extent of nonuniform flux throughout the citric acid cycle are a-ketoglutarate dehydrogenase and mitochondrial aspartate aminotransferase.
Entry of a-ketoglutarate into the second half of
the citric acid cycle (labeled CAC II in Fig. 2) or
diversion into the malate-aspartate cycle appears
to be regulated by the flux through a-ketoglutarate
dehydrogenase. The activity of a-ketoglutarate
dehydrogenase is primarily regulated by the succinyl-CoA-CoA and NADH-NAD ratios (32, 33); an
increased ratio results in inhibition. The succinylCoA-CoA ratio is indirectly regulated by the ATPCirculation Research, Vol. 37, November 1975
529
ADP ratio via substrate-level phosphorylation (at
succinate thiokinase). The NADH-NAD ratio generally reflects the rate of electron transport. Therefore, partition of a-ketoglutarate flux into the citric
acid cycle or the malate-aspartate cycle in response
to the energy state of the myocardium is directed
by the activity of a-ketoglutarate dehydrogenase
(9, 32).
Similarly, oxaloacetate can either enter the first
half of the citric acid cycle (labeled CAC I in Fig. 2)
or bypass it by undergoing transamination with
glutamate. Flux through a second enzyme, aspartate aminotransferase, appears to indirectly regulate this partition of oxaloacetate. Flux through
this enzyme is dependent on the availability of
both oxaloacetate and glutamate. The energylinked glutamate-aspartate exchange carrier, by
regulating transfer of glutamate (and aspartate)
across the inner mitochondrial membrane, may
therefore be primarily responsible for determining
whether oxaloacetate bypasses the first part of the
citric acid cycle. The rate of glutamate transfer by
this carrier is also dependent on the ratio of the
concentrations of glutamate and aspartate in the
cytosol (9, 30, 34). Thus, the metabolic fate of
oxaloacetate is determined not only by reactions of
the citric acid cycle in the mitochondrial compartment but also by the cytosolic levels of key metabolites shared by the malate-aspartate cycle.
Control by these two enzymes, a-ketoglutarate
dehydrogenase and aspartate aminotransferase
(via the aspartate-glutamate carrier), allows flux in
span I and span II of the citric acid cycle to be
transiently dissimilar. As subsequently discussed,
such transient disruptions of uniform flux are
absolutely required for rapid alterations of myocardial citric acid cycle intermediate levels.
ROLE OF THE MALATE-ASPARTATE CYCLE IN THE COORDINATION
OF GLYCOLYTIC AND CITRIC ACID FLUXES
In addition to providing a mechanism for the
oxidation of cytosolic NADH, the malate-aspartate
cycle is required to coordinate mitochondrial and
cytosolic metabolism in the heart. Under a wide
variety of metabolic conditions, balanced glycolytic and citric acid cycle fluxes allow more efficient oxidative metabolism of carbohydrate fuels.
Direct feedback inhibition of glycolysis at phosphofructokinase by citrate and ATP has generally been
accepted as the primary mechanism for this control
(35, 36). Although this mechanism is supported by
kinetic studies of isolated enzymes and changes in
the tissue levels of metabolic intermediates following changes in flux (37), any direct regulation of
530
SAFER
CYTOSOL
MAL
LAC
L PYR
t >s
t
MAnu
NADH
*
OAA
a-KG
TRIOSE-P .
PYR:
GLU
GLUCOSE
a-KG
ISOCIT
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V
INNER
MITOCHONDRIAL
MEMBRANE
MATRIX
CIT
FIGURE 2
Interactions of the malate-aspartate cycle, the glycolytic pathway, and the citric acid cycle which
allow indirect oxidation of cytosolic NADH, rapid alteration of citric acid cycle intermediate levels,
and fine coordination of cytosolic and mitochondrial energy metabolism. The malate-a-ketoglutarate
and aspartate-glutamate exchange carriers, labeled I and II, respectively, are located in the inner
mitochondrial membrane. Two key metabolic branch points at citrate synthetase and a-ketoglutarate dehydrogenase are identified by asterisks. By partitioning total metabolic flux between the
malate-aspartate and citric acid cycles, transiently dissimilar fluxes are allowed in the two
functionally distinct spans of the citric acid cycle (13) designated in the figure as CAC I and CAC II.
The nonuniform citric acid cycle flux in the heart permitted by these two spans is required for rapid
changes in citric acid cycle intermediate levels. A-i indicate key enzymes in these pathways, (a) =
glyceraldehyde-3-phosphate dehydrogenase, (b) = lactate dehydrogenase, (c) = malate dehydrogenase, (d) = aspartate aminotransferase, (e) = citrate synthetase, (f) = aconitase, (g) = isocitrate
dehydrogenase, (h) = a-ketoglutarate dehydrogenase, and (i) = alanine aminotransferase. LAC =
lactate, PYR, = pyruvate, MAL = malate, OAA = oxaloacetate, a-KG = a-ketoglutarate, GLU =
glutamate, ASP = aspartate, ALA = alanine, ISOCIT = isocitrate, CIT = citrate, AcCoA = acetyl
coenzyme A, and TRIOSE-P = glyceraldehyde-3-Pand a-glycerophosphate.
glycolysis by citrate in the heart must reconcile the
virtually complete inability of citrate formed in the
mitochondrial compartment to cross the inner mitochondrial membrane (21, 38) and affect phosphofructokinase in the cytosol. By linking the citric
acid cycle within the mitochondria to the cytosolic
isoenzymes of alanine aminotransferase, isocitrate
dehydrogenase, and aconitase, the malate-aspartate cycle appears to provide a mechanism for rapid
changes in citric acid cycle intermediate levels in
the cytosolic compartment (Fig. 2). This interaction
allows glycolytic flux to be responsive to the redox
state of pyridine nucleotides, the phosphorylation
state of adenine nucleotides, and, thus, the energy
state of the heart (8, 9, 12, 39).
MECHANISM FOR THE ALTERATION OF CITRIC ACID CYCLE
INTERMEDIATE LEVELS IN THE HEART
In addition to being required for changes ir
cytosolic citrate levels, rapid changes in total citrii
acid cycle intermediate levels in the heart appea
to require interaction of the citric acid and malate
aspartate cycles. Increased tissue levels of citrati
cannot be the direct result of an increased rate o
acetyl-CoA entry into the citric acid cycle, sino
two molecules of carbon dioxide are formed pe
cycle turnover and additional oxaloacetate is no
generated. Enzymes required for the carboxylatioi
of pyruvate or acetate are also absent in the hear
(13, 40). Although tissue levels of total citric acii
cycle intermediates and aspartate appear to hav
Circulation Research, Vol. 37, November 19?
531
MALATE-ASPARTATE CYCLE
an inverse relationship to one another, transamination of aspartate cannot directly increase the size of
the citric acid cycle intermediate pool, since
a-ketoglutarate is removed as glutamate in this
reaction. However, the coupled transamination of
aspartate and glutamate by (1) aspartate aminotransferase of the malate-aspartate cycle and (2)
alanine aminotransferase is able to form oxaloacetate in the cytosolic compartment from two metabolic intermediates that are not directly part of the
citric acid cycle intermediate pool (12, 13, 41):
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(1) Aspartate + a-Ketoglutarate •<—»•
Oxaloacetate + Glutamate
(2) Glutamate + Pyruvate-.—>•
Alanine + a-Ketoglutarate
SUM Aspartate + Pyruvater—>•
Oxaloacetate + Alanine
For example, provision of glucose to a substratedeficient heart (12) leads to an increase in the total
citric acid cycle intermediate pool by the following
interaction of the metabolic pathways presented in
Figure 2. An increased cytosolic NADH-NAD ratio,
resulting from greater glycolytic flux, leads to the
rapid reduction of cytosolic oxaloacetate to malate.
This first step results in a displacement of the equilibrium at cytosolic aspartate aminotransferase; by
increasing cytosolic glutamate, this displacement is
in turn transmitted to alanine aminotransferase.
This coupled transamination is responsible for a net
gain in the total tissue citric acid cycle intermediate
pool.
Initially, however, the rate of oxaloacetate formation is severely limited by the availability of
cytosolic a-ketoglutarate required for transamination with aspartate. Additional a-ketoglutarate is
provided by an increased rate of production in the
first span of the citric acid cycle relative to its rate
of entry into the second span. As the result of (1)
greater availability of acetyl-CoA secondary to
increased glycolytic flux and (2) limiting mitochondrial glutamate, the increased rate of mitochondrial oxaloacetate formation is primarily partitioned toward formation of a-ketoglutarate in the
first span of the citric acid cycle. However, because
a-ketoglutarate is exchanged stoichiometrically for
malate across the inner mitochondrial membrane
and both the intramitochondrial NADH-NAD and
ATP-ADP ratios increase (thereby inhibiting
a-ketoglutarate dehydrogenase), this increased mitochondrial a-ketoglutarate production is primarily diverted to the cytosol. Thus, flux in span I of
Circulation Research, Vol. 37, November 1975
the citric acid cycle becomes transient^' greater
than that in span II.
a-Ketoglutarate transferred to the cytosol in this
manner can then be directly utilized for transamination with aspartate. Alternatively, a-ketoglutarate can be reduced to isocitrate by NADP-linked
isocitrate dehydrogenase, with citrate then being
formed via aconitase. In this manner, both the
total tissue content and the intracellular distribution of citric acid cycle intermediates can be
altered. Once equilib. ; um is reestablished at cytosolic aspartate aminotransferase, the tissue level of
citric acid cycle intermediates stabilizes to a new
steady-state level and fluxes in the citric acid and
malate-aspartate cycles become uniform. Since all
of these enzymes present in the cytosolic compartment are fully reversible, changes in the oxidationreduction state of cytosolic pyridine nucleotides
and the metabolic substrate supply can increase or
decrease the tissue levels of citric acid cycle intermediates in this manner.
SIGNIFICANCE OF THE MALATEASPARTATE CYCLE
The central role of the malate-aspartate cycle in
myocardial energy metabolism raises a number of
important questions as to its role in the pathogenesis of and the compensatory response to a number
of disorders of myocardial function. It has been
demonstrated, for example, that generalized inhibition of the malate-aspartate cycle can produce
idiopathic lactic acidosis (8, 42, 43). Such inhibition in the heart can also have profound direct and
indirect effects on contractility, since both excitation-contraction coupling and the malate-aspartate cycle appear to be inhibited by acidosis
(44-49). By decreasing the oxidative metabolism of
glucose, which requires the malate-aspartate cycle,
localized acidosis can also contribute to contractile
failure and affect survival of the ischemic myocardium. Although such suggestions are highly speculative at the present time, further research in these
areas appears to be warranted.
Acknowledgment
I gratefully acknowledge the support, encouragement, and
useful discussions provided by Dr. John R. Williamson and his
associates at the Johnson Research Foundation, who contributed significantly to the organization and the scope of this
review.
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The Metabolic Significance of the Malate-Aspartate Cycle in Heart.
B Safer
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Circ Res. 1975;37:527-533
doi: 10.1161/01.RES.37.5.527
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