Phosphotransfer networks and cellular energetics
Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA
* Author for correspondence (e-mail: dzeja.petras{at}mayo.edu)
Accepted 3 April 2003
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Summary |
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Key words: energy, metabolism, mitochondria, creatine kinase, adenylate kinase, glycolysis, carbonic anhydrase, homeostasis
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Introduction |
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Intracellular energy transfer |
---|
The localization of mitochondria in close proximity to cellular
energy-utilizing processes, and their movement in response to activation of
ATP-utilizing reactions (Hollenbeck,
1996), suggest that the distance of energy transfer is critical
for adequate energy supply. However, energy transfer by diffusional exchange
of adenine nucleotides is kinetically and thermodynamically inefficient since
it requires a significant concentration gradient
(Meyer et al., 1984
;
Jacobus, 1985
), and would
result in ATPase inhibition by end products (Pi, ADP,
H+), inability to sustain the high free energy of ATP hydrolysis
(
GATP) at sites of ATP utilization
(Fig. 1), and ultimately energy
dissipation (
H) during transmission
(Kammermeier, 1997
;
Dzeja et al., 2000
). The
difference between
G1(ATP) and
G2(ATP), signifying energy loss
(
H), would increase at higher rates of ATP turnover, and the
drop of
G2(ATP) below a threshold would impair cellular functions
(Kammermeier, 1997
;
Taegtmeyer, 2000
).
|
Part of intracellular energy transfer proceeds in the narrow mitochondrial
inner membrane infoldings, known as cristae
(Fig. 2). The cristae
arrangement increases, by several folds, the capacity of mitochondrial ATP
production without occupying additional intracellular space. However, it
creates difficulties in ATP export from the mitochondrial intracristal space,
as diffusional flux requires a significant concentration gradient.
Accordingly, ATP accumulation in the mitochondrial intracristal space would
inhibit export of ATP from the mitochondrial matrix by locking the adenine
nucleotide translocator (Mannella et al.,
2001). In principle, this limitation can be overcome by either
placing in the intracristal space near-equilibrium phosphotransfer systems,
capable of accelerating ATP export/ADP import, and/or by establishing
high-throughput contact sites between inner and outer membranes, thereby
providing direct access to ATP in the mitochondrial matrix
(Fig. 2). Available data
suggest that in mitochondrial physiology both possibilities are employed, and
their functional significance may vary depending on the physiological
conditions or functional load (Gerbitz et
al., 1996
; Ziegelhoffer, 2002). This view is supported by the
observation that the presence of creatine kinase, adenylate kinase and
nucleoside diphosphate kinase in the intermembrane space facilitates ATP/ADP
exchange between mitochondria and cytosol
(Saks et al., 1994
;
Laterveer et al., 1997
;
Roberts et al., 1997
;
Dzeja et al., 1999b
).
Conversely, disruption of the adenylate kinase gene impedes ATP export from
mitochondria (Bandlow et al.,
1988
). Taken together, this would indicate that in the absence of
facilitating mechanisms, cell architecture and diffusional hindrances would
obstruct free movement of molecules, impeding efficient intracellular
communication.
|
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Near-equilibrium enzymatic flux transfer networks |
---|
Produced by the ATPase reactions, ADP apparently cannot diffuse freely and
serve as a feedback signal to ATP-regenerating processes, as abundant and
catalytically active creatine kinase, adenylate kinase and glycolytic enzymes
residing throughout a cell would process a large portion of the ADP produced
by ATPase reactions (Saks et al.,
1994; Dzeja et al.,
2000
). The high rate of unidirectional phosphoryl exchange in
these phosphotransfer systems would promote metabolic flux wave propagation
and ligand conduction at cellular distances.
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Creatine kinase phosphotransfer system: a conduit for high-energy phosphoryls |
---|
Understanding of creatine kinase function was limited when the cell was
considered as a homogenous system where enzymes are in equilibrium, and
metabolites have uniform distributions and concentrations
(Meyer et al., 1984;
Kushmerick, 1995
). Recently, a
new experimental approach that allows quantification of unidirectional fluxes
of creatine kinase localized in different subcellular compartments provided
strong evidence for the involvement of creatine kinase in intracellular energy
transfer (Joubert et al.,
2002
). Moreover, transgenic animal studies demonstrate that
creatine kinase deficiency compromises energy delivery for muscle contraction
and intracellular calcium handling, as well as signal communication to
membrane metabolic sensors such as the KATP channel
(van Deursen et al., 1993
;
Steeghs et al., 1997
;
Saupe et al., 1998
;
Kaasik et al., 2001
;
Abraham et al., 2002
).
In creatine kinase-deficient muscles, phosphotransfers catalyzed by
adenylate kinase as well as by glycolytic enzymes provide the major route for
intracellular high energy phosphoryl transfer (Dzeja et al.,
1998,
2003
;
de Groof et al., 2001
). Such
alternative high-energy phosphoryl routes may rescue cellular bioenergetics in
cells with compromised creatine kinase (CK)-catalyzed phosphotransfer
(Boehm et al., 2000
;
Dzeja et al., 2000
). In this
regard, observations following deletion of brain B-CK indicate that this
isoform is fundamental to processes that involve habituation, spatial learning
and seizure susceptibility (Jost et al.,
2002
). Mitochondrial isoforms ScCKmit and UbMi-CK are critically
necessary to maintain normal high-energy phosphate metabolite levels in heart
and brain during stress (Kekelidze et al.,
2001
; Spindler et al.,
2002
). In addition, reduction in cellular B-CK activity by
dominant negative gene expression abrogates thrombin-mediated,
energy-dependent signal transduction during cytoskeletal reorganization
(Mahajan et al., 2000
). These
findings emphasize the importance of creatine kinase in providing energetic
efficiency in support of various cellular functions.
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Adenylate kinase phosphotransfer system: managing ß- and
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---|
Recent evidence indicates that the adenylate kinase-catalyzed relay indeed
facilitates intracellular energetic communication, and that loss of adenylate
kinase function can be complemented by activation of creatine kinase
phosphotransfer (Carrasco et al.,
2001; Dzeja et al.,
2002
). Moreover, interaction between adenylate kinase and creatine
kinase phosphorelays determines metabolic signal transmission to the
prototypic membrane metabolic sensor, the KATP channel
(Dzeja and Terzic, 1998
;
Carrasco et al., 2001
;
Abraham et al., 2002
), and
mediates energetic remodeling in preconditioned
(Pucar et al., 2001
) and
failing hearts (Dzeja et al.,
1999b
,
2000
). AK1 knockout muscles
display lower energetic efficiency and increased vulnerability to metabolic
stress, associated with a compromised ability to maintain nucleotide pools and
intracellular metabolic signal communication
(Janssen et al., 2000
;
Pucar et al., 2002
). Also,
muscle exercise performance correlates with adenylate kinase activity,
suggesting that this enzyme is an integral part of cellular energetic
homeostasis (Linossier et al.,
1996
).
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Glycolytic phosphotransfer system: delivering mitochondrial high-energy phosphoryls in exchange for Pi, NADH and ADP |
---|
|
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Carbonic anhydrase ligand conduction system: speeding up protons and disposing of CO2 |
---|
As most ATPases, especially actomyosin ATPase, are inhibited by the buildup
of protons in their vicinity, the necessity for H+ removal system
is warranted (Dzeja et al.,
1999a). In this regard, inhibition of carbonic anhydrase reduces
muscle contractility and calcium handling
(Geers and Gros, 1991
), and
could contribute to the development of heart failure
(Dzeja et al., 1999a
). It was
proposed that sequentially arranged carbonic anhydrase molecules catalyzing
rapid equilibrium among reactants could provide ligand conduction pathways for
transferring protons from ATPases to ATP-generating sites inside the cell, as
well as for facilitated transfer of CO2 to the cell membrane and
consequently out of the cell to the capillaries
(Dzeja et al., 1999a
). In
fact, 'proton waves' have been observed to spread throughout the entire cell
and also from one cell to another (Grandin
and Charbonneau, 1992
; Mair
and Muller, 1996
).
The creatine kinase phosphotransfer system can also participate in proton
transfer from ATPases (Fig. 3),
and its function may be interrelated with that of carbonic anhydrase
(Wallimann et al., 1998; Dzeja et al.,
2000). In this regard, creatine kinase deficient muscles have a
reduced capability to regulate intracellular pH
(in't Zandt et al., 1999
).
Thus, carbonic anhydrase is emerging as a dynamic player in intracellular and
paracellular H+ and CO2 trafficking, and as an integral
part of the cell energetic infrastructure.
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Nucleoside diphosphate kinase system: energy currency exchange, delivery and feedback signaling |
---|
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Phosphotransfer systems and nuclear processes: trading metabolic energy for information |
---|
These data implicate phosphotransfer enzymes in the energy-linked
regulation of matter and information exchange between the cytosol and nucleus
(Fig. 4). In this way,
sequential phosphotransfers are responsible for transmission of ATP and GTP
from mitochondria and maintenance of ATP/ADP and GTP/GDP ratios at
ATP/GTP-utilization sites. Variations of phosphotransfer enzyme activity in
the cytosol and nucleus correlate with the intensity of nuclear processes in
normal and diseased conditions, underscoring the significance of maintained
phosphotransfer in directing cellular energy flow
(Manos and Bryan, 1993;
Dzeja et al., 2000
;
Perez-Terzic et al., 2001
). In
this regard, glycolytic enzymes have also been identified in nuclei of several
cell types, including regenerating hepatocytes where they furnish a
considerable portion of increased nuclear energy requirements
(Ottaway and Mowbray, 1977
).
Thus, integration of the nuclear compartment with mitochondrial energetics is
accomplished through specialized enzymatic networks, securing the metabolic
demands of nuclear processes.
|
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Concluding remarks |
---|
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Acknowledgments |
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