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Mitochondria-Nucleus Energetic Communication: Role for Phosphotransfer Networks in Processing Cellular Information.


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Metabolic networks composed of the creatine kinase, adenylate kinase, and glycolytic phosphotransfer reactions are integral components of the cellular energetic infrastructure. Collectively, these pathways facilitate transfer and distribution of high-energy phosphoryls produced in the mitochondria through structured cytosolic and nuclear compartments. In this way, intracellular phosphotransfer relays secure efficient energetic and metabolic signaling, and thereby determining the fidelity of a range of cellular responses, including nucleocytoplasmic, metabolic, and genomic communications. The role and contribution of individual phosphotransfer enzymes depends on the species, tissue, developmental stage, or (patho) physiological state, underscoring the plasticity of the cellular energetic system in governing metabolic homeostasis. Catalyzed phosphotransfer along with related systems such as nucleoside diphosphate kinase (NDPK) play a vital role in organs with intense and fluctuating energy and signaling demands such as the heart or brain. Deletion of phosphotransfer enzyme isoforms compromises diverse cellular functions, including metabolic signaling, information processing, and adaptation of cellular energy metabolism to stress. Adaptive genetic reprogramming in conditions of phosphotransfer enzyme deficits is required to safeguard optimal cellular energetics. Emerging data indicate that coupling of phosphotransfer enzymes with metabolic sensors and phosphoryl-transferring protein kinase cascades comprises a unified intracellular energy/signal transduction matrix capable of processing, delivering, and retrieving cellular information. Here, recent evidence demonstrating the significance of compartmentalized and dynamically superimposed interactions of adenylate kinase, creatine kinase, and glycolytic enzyme-catalyzed phosphotransfers in orchestrating cytosolic and nuclear energetics is highlighted.
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6.3 Mitochondria-Nucleus Energetic
Communication: Role for
Phosphotransfer Networks in
Processing Cellular Information
P. P. Dze j a .A. Terzic
1 Introduction ...................................................................................... 642
2 Mechanisms of Intracellular Energetic Communication ........................................ 643
2.1 Simple Diffusion . . . . . . . . . . . . . . . . . . ..................................................................645
2.2 Facilitated Diffusion . . . . . . . . . . . . . . .................................................................. 645
2.3 Metabolite Channeling . . . . . . . . . . . . .................................................................. 646
2.4 ReactionDiffusion . . . . . . . . . . . . . . . . ..................................................................646
2.5 Ligand Conduction . . . . . . . . . . . . . . . ..................................................................647
3 Phosphotransfer Reactions in MitochondrialNuclear Energetic Communication ............. 648
4 PhosphotransferMediated Metabolic Signaling ................................................. 651
5 Phosphotransfer Networks in Processing and Integrating Cellular Information ............... 654
6 Concluding Remarks .............................................................................657
#Springer-Verlag Berlin Heidelberg 2007
Handbook of Neurochemistry and Molecular Neurobiology
Brain Energetics. Integration of Molecular and Cellular Processes
Editors: Abel Lajtha, Gary E. Gibson Ph.D., Gerald A. Dienel Ph.D. ,
Springer, 2007, Ch 6.3, pp 641-666.
Abstract: Metabolic networks composed of the creatine kinase, adenylate kinase, and glycolytic phospho-
transfer reactions are integral components of the cellular energetic infrastructure. Collectively, these path-
ways facilitate transfer and distribution of highenergy phosphoryls produced in the mitochondria through
structured cytosolic and nuclear compartments. In this way, intracellular phosphotransfer relays secure
efficient energetic and metabolic signaling, and thereby determining the fidelity of a range of cellular
responses, including nucleocytoplasmic, metabolic, and genomic communications. The role and contribu-
tion of individual phosphotransfer enzymes depends on the species, tissue, developmental stage, or (patho)
physiological state, underscoring the plasticity of the cellular energetic system in governing metabolic
homeostasis. Catalyzed phosphotransfer along with related systems such as nucleoside diphosphate kinase
(NDPK) play a vital role in organs with intense and fluctuating energy and signaling demands such as the
heart or brain. Deletion of phosphotransfer enzyme isoforms compromises diverse cellular functions,
including metabolic signaling, information processing, and adaptation of cellular energy metabolism to
stress. Adaptive genetic reprogramming in conditions of phosphotransfer enzyme deficits is required to
safeguard optimal cellular energetics. Emerging data indicate that coupling of phosphotransfer enzymes
with metabolic sensors and phosphoryltransferring protein kinase cascades comprises a unified intracel-
lular energy/signal transduction matrix capable of processing, delivering, and retrieving cellular informa-
tion. Here, recent evidence demonstrating the significance of compartmentalized and dynamically
superimposed interactions of adenylate kinase, creatine kinase, and glycolytic enzymecatalyzed phospho-
transfers in orchestrating cytosolic and nuclear energetics is highlighted.
List of Abbreviations: AMPK, AMP-activated protein kinase; GAPDH, glyceraldehydes-3-phosphate
dehydrogenase; b-GPA, beta-guanidinopropionic acid; K
, ATP-sensitive potassium channel; NDPK,
nucleoside diphosphate kinase; PFK, phosphofructokinase
1 Introduction
Efficient coordination of energy supply and demand, secured through metabolic signaling, is central for
normal cell function and stress response. Phosphotransfer networks, composed of adenylate kinase, creatine
kinase, nucleoside diphosphate kinase (NDPK), and glycolytic enzymes, have emerged as prototypic
intracellular energetic signaling pathways integral to the maintenance of cellular homeostasis (Wallimann
et al., 1992; Saks et al., 1994; de Groof et al., 2001; Dzeja and Terzic, 2003; Ingwall, 2004). These networks
facilitate communication of highenergy phosphoryls and metabolic signals between cellular compart-
ments, adjusting cellular energy flux in response to functional load (Dzeja et al., 1998, 2004; Boehm et al.,
2000; Janssen et al., 2000, 2003b; Saks et al., 2004). As such, the governance of ATPrequiring and ATP
responding cellular components and their integration with cellular energetic and signaling systems is
accomplished through the dynamics of phosphotransfermediated intracellular nucleotide exchange
(Dzeja and Terzic, 1998; Carrasco et al., 2001; Abraham et al., 2002; Neumann et al., 2003; Allen and
DunawayMariano, 2004). Efficient intracellular energetic communication is of particular importance in
organs with sudden and fluctuating energy demands such as the heart and brain (Wallimann and Hemmer,
1994; Dzeja et al., 1999a; Ames, 2000; Kekelidze et al., 2001; Jost et al., 2002). A case in point is the energy
transfer in photoreceptors and neurons, where ATPgenerating and ATPconsuming processes are separated
by large distances (Hemmer et al., 1993; Notari et al., 2001; Streijger et al., 2004). Similarly, the energy
demands of the contracting muscle require efficient communication of energetic signals (Saks et al., 1994;
Dzeja and Terzic, 2003).
The distribution of metabolic flux among individual phosphotransfer systems, under different meta-
bolic states, could in turn regulate vital ATPsensitive cellular processes, including ion conduction, nuclear
cytoplasmic information exchange, receptormediated signal transduction, cytoskeletal organization, and
cell motility (Mahajan et al., 2000; Abraham et al., 2002; Dzeja et al., 2002; Hipe et al., 2003; Picher and
Boucher, 2003). The interaction with adenylate kinase and creatine kinase has been directly implicated in
the activity of diverse metabolic sensors, such as the AMPactivated protein kinase (AMPK) and the ATP
sensitive potassium (K
) channel, and in the overall ability of the cell to withstand metabolic stress
642 6.3 Mitochondria-nucleus energetic communication
(Dzeja et al., 1998; Bergeron et al., 2001; Carrasco et al., 2001; Pucar et al., 2001; Zingman et al., 2001,
2002b; Hardie, 2003; Pucar et al., 2004; Alekseev et al., 2005). Metabolic and functional alterations induced
by transgenic deficiency of individual phosphotransfer isoforms precipitate a broad spectrum of genetic
reprogramming with a resulting wide range of cellular adaptations, underscoring the fundamental role of
energetic pathways in sustaining efficient yet vibrant cellular energetics (van Deursen et al., 1993; Saupe
et al., 1998; Janssen et al., 2000, 2003a; Dzeja et al., 2004). Moreover, recent geneknockout studies, where
single or multiple phosphotransfer enzymes are disrupted, have opened new perspectives in the intimate
understanding of cellular energetic and metabolic signaling networks and their integration with genetic,
biosynthetic, membrane electrical, and receptormediated signal transduction events within the cellular
environment (Steeghs et al., 1997; Boehm et al., 2000; Pucar et al., 2000, 2002; Dzeja and Terzic, 2003;
Ingwall, 2004; Spindler et al., 2004). Taken together, with the emerging identification of scaffolding proteins
and their support of the spatial organization of phosphotransfer networks, the efficiency and specificity of
highenergy phosphoryl distribution has been recognized as necessary in securing a harmonious coordina-
tion of diverse cellular processes (Dzeja et al., 2000; Horneman et al., 2003; Neumann et al., 2003; Saks et al.,
2004; Dzeja and Terzic, 2005). A case in point is the adaptor protein DRAL/FHL2, involved in the
anchoring of creatine kinase, adenylate kinase, and phosphofructokinase (PFK) to sites of highenergy
consumption in the cardiac sarcomere (Lange et al., 2002). Similarly, the Oda5p protein anchors adenylate
kinase in the proximity of the dynein arm ensuring that both the highenergy phosphate bonds of ATP are
efficientlyutilized at the major site of powerproductionof the microtubule motors that are involved in diverse
cellular movements (Wirschell et al., 2004). In this regard, overexpression of adenylate kinase isoforms
contributes to the precise movements of the extraocular muscle (Andrade et al., 2003). We here summarize
recent evidence regarding the importance of phosphotransfer networks in the regulation of the mitochondrial
nuclear energetic communication, metabolic signaling, and processing of cellular information.
2 Mechanisms of Intracellular Energetic Communication
In the cell, major sites of energy transformation and ATP production are spatially separated from sites of
ATP energy utilization that support vital cellular functions. Progress has been made in elucidating the
cytoarchitectural, convectional, and enzymatic mechanisms that facilitate the coupling and coordination of
energy transduction processes with the metabolic, mechanical, and electrical activities of the cell
(Hochachka, 1999; Janssen et al., 2000; Kaasik et al., 2001; Saks et al., 2001; Abraham et al., 2002; Selivanov
et al., 2004). Cytoplasmic streaming, positioning of mitochondria and their movement in response to
changes in energy utilization, along with formation of enzymatic and mitochondrial–myofibrillar com-
plexes, have all been shown to contribute to the facilitation of intracellular energetic communication
(Harold, 1991; Hollenbeck, 1996; Hochachka, 1999; Lange et al., 2002; Saks et al., 2004). However,
topological arrangements apparently are not sufficient on their own to fulfill cellular energetic needs
(Boehm et al., 2000; Dzeja et al., 2000; de Groof, 2001; Dzeja and Terzic, 2003). In this regard, a new role
has emerged for spatially arranged intracellular enzymatic networks catalyzed by creatine kinase, adenylate
kinase, and glycolytic enzymes, supporting highenergy phosphoryl transfer and signal communication
between ATPgenerating and ATPconsuming/ATPsensing processes (Wallimann et al., 1992; Saks et al.,
1994; Dzeja et al., 1998, 2000, 2004; Joubert et al., 2002; Ingwall, 2004) (>Figure 6.3-1).
Creatine kinase is a major phosphotransfer system in cells with highenergy demand, and it acts in
concert with other enzymatic systems to facilitate intracellular energetic communication (Bessman and
Carpenter, 1985; Jacobus, 1985; Saks et al., 1994; Joubert et al., 2002; Dzeja and Terzic, 2003; Neumann
et al., 2003). Energy transfer does not exclusively rely on creatine kinase (Zeleznikar et al., 1995; Dzeja
et al., 1998, 1999b, 2004; Boehm et al., 2000; Janssen et al., 2000, 2003b). Parallel to the creatine kinase
system is the adenylate kinasecatalyzed highenergy phosphoryl shuttle (>Figure 6.3-1), which provides
a unique capability for transfer and utilization of both band gphosphoryls of the ATP molecule,
doubling its energetic potential (Dzeja et al., 1985, 1996, 1999b; Zeleznikar et al., 1990). Tissues with
highenergy demands are also characterized by robust phosphoryl exchange catalyzed by glycolytic
phosphotransfer enzymes (KingsleyHickman et al., 1987; Portman, 1994). Depending on metabolic
Mitochondria-nucleus energetic communication 6.3 643
needs, there is a tight regulation of glycolytic enzyme binding to the mitochondrial outer membrane and to
cellular ATPconsumption sites (Gerbitz et al., 1996; Cesar and Wilson, 1998; Ikemoto et al., 2003).
This facilitates highenergy phosphoryl transfer from mitochondria to sites of ATP utilization through
the glycolytic network (Dzeja et al., 2004). Energyrich phosphoryls from ATP, used to phosphorylate
glucose and fructose6phosphate at the mitochondrial site, traverse the glycolytic pathway and can be
used to phosphorylate ADP through pyruvate kinasecatalyzed reactions at remote ATPutilization sites
(>Figure 6.3-1). There is a close functional interaction and potential for substitution between creatine
kinase, adenylate kinase, and glycolytic phosphotransfer systems (Dzeja and Terzic, 2003). Indeed, such
alternative highenergy phosphoryl routes may rescue cellular bioenergetics under conditions of compro-
mised creatine kinasecatalyzed phosphotransfer (Dzeja et al., 2004). The glycolytic phosphotransfer system
has a distinct significance in brain energetics (as discussed in Chapter 4) supporting ATPdependent
processes separated from mitochondria at much larger distances compared with nonneuronal cells
(Ames, 2000; Gjedde, 2001). The function of the newly discovered adaptor protein DRAL/FHL2, which
is involved in anchoring creatine kinase, adenylate kinase, and glycolytic enzymes to sites of highenergy
consumption (Lange et al., 2002), is apparently to maintain the structural integrity of the intracellular
phosphotransfer network (>Figure 6.3-1). Mutations in the FHL2 family of proteins are associated with
human heart disease (Lange et al., 2002). The expression of FHL family proteins is not detected in the brain
where other principles or distinct anchoring proteins could be involved in the topological arrangement of
intracellular phosphotransfer networks. As such, membrane anchoring of phosphotransfer enzymes
.Figure 6.3-1
Integrated cellular phosphotransfer network facilitates high-energy phosphory1 export from mitochondria,
with delivery and distribution to remote cellular ATPases. High-energy phosphoryls (~P), produced in mito-
chondria, are exported into the cytosol and delivered to remote cellular ATPases. Delivery is mediated and
facilitated by three major phosphotransfer reactions comprising the intracellular phosphotransfer network.
Network infrastructure is maintained by the interaction of phosphotransfer enzymes with cellular constituents
mediated by specific protein domains, protein acetylation, myristoylation, and by anchor proteins (e.g., DRAL/
FHL-2). MI-CK and M-CK, mitochondrial and cytosolic isoforms of CK, respectively; AK1 and AK2, cytosolic and
mitochondrial isoforms of AK, respectively; AK3, mitochondrial matrix AK isoform; ANT, adenine nucleotide
translocator; Hex, hexokinase; DRAL/FHL-2, phosphotransfer enzyme anchor LIM domain protein; i.m. and o.m.,
inner and outer membranes, respectively
644 6.3 Mitochondria-nucleus energetic communication
through protein alkylation or phosphorylation could provide organized phosphotransfer pathways to syn-
chronize energy supply to membrane ATPases, and thus harmonizing the operation of ATP/ADPsensitive
receptors and ion channels, important components ofthe brain cell function (Wallimann and Hemmer, 1994;
Dzeja and Terzic, 1998; Janssen et al., 2004). Indeed, membranebound creatine kinases and adenylate kinases
are characteristic for brain cell types (Nagy et al., 1989; Wallimann and Hemmer, 1994; Inouye et al., 1999).
Energy transfer and feedback signal communication through the exchange of nucleotides and other
highenergy carrying molecules between ATPconsuming and ATPproducing processes could be accom-
plished by several mechanisms. These are described individually in the following sections.
2.1 Simple Diffusion
Diffusion is an intrinsic feature of molecular processes determining random movement of molecules down
the concentration gradient. In the cellular environment, simple diffusion of molecules is hampered by high
structural organization and viscosity of the cytoplasm (LubyPhelps, 2000; Vendelin et al., 2004). Formula-
tions of diffusional fluxes have been developed to account for such high density, inhomogeneous, and
spatially confined environments (Andreucci et al., 2003; Roussel and Roussel, 2004). The localization of
mitochondria in close proximity with cellular energyutilizing processes and their movement in response to
activation of ATPutilizing 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; Dzeja et al., 1999b). This would result in ATPase inhibition by end
products (P
, ADP, H
), the inability to sustain free energy of ATP hydrolysis (DG
) at sites of ATP
utilization at an appropriate magnitude above the threshold value, and ultimately in energy dissipation
during transmission (Kammermeier, 1997; Dzeja et al., 2000; Dzeja and Terzic, 2003). A low concentration
of intracellular ADP, necessary to sustain a high ATP/ADP ratio and DG
, is considered the limiting
factor in diffusional feedback communication from ATPases to mitochondrial oxidative phosphorylation
(Jacobus, 1985; Saks et al., 2003). Also, diffusional nucleotide exchange cannot provide a uniform energy
supply to all ATPases such as in the center of myofibrils, where ATP deficiency can cause formation of rigor
bridges (VenturaClapier and Veksler, 1994). To achieve normal contraction of isolated myofibers, about ten
times higher concentration of bulk ATP should be provided (Bendall, 1969). The same is true with DNA
synthesis where much higher concentrations of deoxyribonucleotides are required in vitro compared with
conditions in vivo (Mathews, 1985). If all energyrequiring cellular processes competed for a common pool
of ATP, one low K
/high V
ATPase might effectively eliminate access of other processes to ATP (Masters,
1991). Thus, in the intracellular environment, diffusional exchange of molecules and even small ions is
restricted, and concentration gradients build up (Kemp et al., 1998; Kongas and van Beek, 2002). Diffu-
sional restrictions for water molecule movement in the brain are used for tissue microarchitecture and
microdynamic imaging using diffusion tensor NMR (Le Bihan, 2003). Molecular diffusion is impaired in
disease processes such as brain ischemia (Le Bihan, 2003), and a reduced diffusivity of signaling molecules
within the brain’s interstitial space due to amyloid deposits contributes to the cognitive impairment in
Alzheimer’s disease (Mueggler et al., 2004).
2.2 Facilitated Diffusion
Facilitated diffusion is a carriermediated process for accelerated transport of molecules across imperme-
able membranes or throughout the cellular cytosol and extracellular space. According to this mechanism,
reversible combination of a ligand with a protein macromolecule results in enhancement of diffusion due to
fluxes of both freeand carrierbound ligand (Wittenberg, 1970). This type of mechanism has been applied
to myoglobinand hemoglobinfacilitated oxygen diffusion (Wittenberg, 1970) as well as to creatine kinase
(Meyer et al., 1984) and carbonic anhydrase (Enns, 1967; Stewart et al., 1999) reactions with regard to
accelerated metabolite and ion transfer. In the latter, the diffusive flux of substance X in one metabolic
Mitochondria-nucleus energetic communication 6.3 645
pathway is effectively increased when it participates in an equilibrium reaction with another substance Y
since the total flux of X in the pathway is the sum of X and Y fluxes (Meyer et al., 1984). However, this is
likely more a reflection of the reactiondiffusion mechanism associated with the reaction front or disequi-
librium movement and flux wave propagation (Goldbeter and Nicolis, 1976; Vandelin et al., 2000). Also, the
classic example of myoglobinfacilitated oxygen diffusion has been lately questioned due to findings of
relatively low mobility of myoglobin in the crowded muscle cytosol (Jurgens et al., 1994; Wittenberg and
Wittenberg, 2003). Measurements of intracellular distribution of myoglobin show that this protein displays
a clustered pattern of localization parallel to mitochondrial arrays (Takahashi and Asano, 2002). Even
immobilized hemoglobin or carbonic anhydrase can markedly increase the rate of O
or CO
(Hemmingsen, 1962; Trachtenberg et al., 1999), which is consistent with the proposed ligand conduction
mechanism rather than facilitated diffusion (Dzeja and Terzic, 2003).
2.3 Metabolite Channeling
In living cells, there are numerous stable enzymatic complexes where metabolites are transferred directly
from one to the other consecutive component without equilibration with the common intracellular pool
(Welch and Easterby, 1994; Ovadi and Saks, 2004). The occurrence of channeling or direct transfer through
transient association of enzymes during metabolic activity has important kinetic as well as regulatory
implications (Saks et al., 1994; Welch and Easterby, 1994). Selective channeling of intermediates increases
the economy and efficiency of enzymatic processes and enables preferential routing of metabolic fluxes
through branched pathways in the crowded cellular environment (Srivastava and Bernhard, 1987; Aflalo,
1991; Ovadi and Saks, 2004). In principle, metabolite channeling or the ‘‘bucket brigade’’ type of action
could occur between associated single ty pes of phosphotransfer enzymes forming molecular wires or clusters
(Wallimann et al., 1992; Appleby et al., 1996; Dzeja and Terzic, 1998). In this regard, direct metabolite
channeling has been demonstrated between complexes of phosphotransfer enzymes with the adenine nucleo-
tide translocator in mitochondria as well as with cellular ATPases (Saks et al., 1994). It is unresolved whether
substrate channeling is effective at longer distances within enzymatic clusters. In the cytosolic compartment
and in the mitochondrial intermembrane space, sequential phosphotransfer reactions could operate through
the mechanism of reactiondiffusion or ligand conduction (Dzeja et al., 1998; Dzeja and Terzic, 2005).
2.4 ReactionDiffusion
In biological and chemical systems which are not well mixed, enzymatic and chemical reactions are
associated with substrate and product diffusion, triggering reaction front propagations, inhomogeneous
spatial concentration patterns, and chemical or metabolic waves (Goldbeter and Nicolis, 1976; Mair and
Muller, 1996; Vandelin et al., 2000). Reactiondiffusion phenomena have a broad biological significance,
regulating the spatiotemporal behavior of genetic, metabolic, and electrophysiological processes (Saks et al.,
2000, Roussel and Roussel, 2004; Selivanov et al., 2004). In searching how cells overcome diffusional
limitations for energy transfer in the highly structured intracellular milieu, it has been suggested that the
displacement of equilibrium of creatine kinase or glycolytic reactions in one cellular locale could be rapidly
transmitted through a nearequilibrium network in the form of a sharp concentration wavefront over
macroscopic distances (Nagle, 1970; Goldbeter and Nicolis, 1976). This has led to the concept of flux
transfer chains along which an incoming flux wave could be instantaneously transmitted in either direction
(Reich and Sel’kov, 1981), as well asto the node of a ‘‘phosphocreatine circuit’’ (Wallimann et al., 1992). It is
known that flux wave propagation along rapid equilibrating chemical and biological reactions can proceed
much faster than diffusion of reactants (Goldbeter and Nicolis, 1976; Mair and Muller, 1996). The rate of
wave front movement in these systems is equal to the square root of the reaction velocity constant and the
diffusion coefficient (Mair and Muller, 1996). These calculations provide an important indication why the
total activity of many enzymes catalyzing nearequilibrium reactions in the cell surpasses apparent physio-
logical needs (Saks et al., 1994). Reactiondiffusion models have been successfully applied to describe the
646 6.3 Mitochondria-nucleus energetic communication
organization and dynamic behavior of the complex cellular energetic system (Meyer et al., 1984; Wallimann
et al., 1992; Kemp et al., 1998). Indeed, ‘‘metabolic waves’’ have been observed to propagate rapidly
throughout the entire cell (Mair and Muller, 1996; Kindzelskii and Petty, 2002) and oscillations in energy
metabolism appear to govern cellular electrical activity, biological information processing, and functional
response (O’Rourke et al., 1994; Welch, 1996; Dzeja and Terzic, 2003). The phosphotransfer enzyme adenylate
kinase is one of the principal components in the generation of metabolic oscillations by sustaining dynamic
fluctuations of adenine nucleotide ratios (Welch, 1977; Mair and Muller, 1996). In this regard, a term,
excitable ‘‘adenylate kinase medium’’ has been proposed (Kohen et al., 1985) to emphasize the significance of
this enzyme in conveying energetic and metabolic signals (Carrasco et al., 2001; Dzeja et al., 2002).
2.5 Ligand Conduction
Ligand conduction stems from the proton conduction mechanism (Grotthuss mechanism), a much faster
transfer of protons in strong acid solutions compared with simple diffusion (Pomes and Roux, 2002). This
phenomenon, which was recently refined using modern computer simulation, is referred to as ‘‘walking
without moving’’ (Tuckerman et al., 2002). According to the ligand conduction mechanism, a triggering
ligand induces a series of propagations in a coupled system resulting in the almost instantaneous appear-
ance of an equivalent ligand at the distant end. Ligand conduction occurs along spatially oriented water and
protein molecules (‘‘proton wires’’) (Pomes and Roux, 2002), in transmembrane ion channels (singlefile
ion conduction) (Berneche and Roux, 2001), in the mitochondrial respiratory chain (electron and proton
conduction) (Mitchell, 1979), in vascular plants, aquaporin channels and carbon nanotubes (water
conduction) (TournaireRoux et al., 2003; Zhu and Schulten, 2003; Agre et al., 2004), and in the extracel-
lular space and fluid channels of the inner ear (fluid conduction) (Mhatre et al., 2002; Pozrikidis and
Farrow, 2003; Mueggler et al., 2004). Bacterial phosphorelaytype sugar transport, signal transduction
through receptor–Gprotein–protein kinase cascades, and propagation of conformational changes through
linear chains of protein molecules apparently also occur by ligand or structural conduction mechanisms
(Appleby et al., 1996; Lu et al., 1996; Bray and Duke, 2004). In addition, myoglobinand hemoglobin
facilitated oxygen diffusion could be accomplished through the ligand conduction mechanism by ‘‘hop-
ping’’ of oxygen molecules along the network of relatively immobile carrier molecules (Takahashi and
Asano, 2002). This is indicated from direct measurements of oxygen diffusion using
O isotopes (Hem-
mingsen, 1962) and from other considerations (Wittenberg and Wittenberg, 2003). Ligand conduction
mechanism is also suggested for the carbonic anhydrasecatalyzed intracellular and paracellular CO
and H
O transfer pathways (Dzeja and Terzic, 2003). In this regard, carbonic anhydrase networks by
forming planar H
conduction pathways along cell surface or mucosa, which could prevent direct H
entrance and protect cells from acid damage (Kivela et al., 2005; Marcus et al., 2005). Thus, growing
evidence suggests the versatility of ligand conduction in different cellular processes.
By addressing vectorial behavior of chemiosmotic systems, the principle of vectorial ligand conduction
has been formulated as a basic mechanism for operation of metabolic and transport processes within the
cell (Mitchell, 1979). According to this principle, ‘‘vectorial metabolism’’ is represented by a network of
spatiotemporal pathways along which ligands, including solutes, ions, chemical groups, electrons, and
catalytic compounds and complexes, are conducted by articulated movements that occur in the direction of
the thermodynamically natural escaping tendency (Mitchell, 1991). Subsequently, this principle was
applied to the chains of sequential rapid equilibrating reactions catalyzed by creatine kinase and adenylate
kinase (‘‘phosphoryl wires’’) as a mechanism for facilitated highenergy phosphoryl transfer between ATP
consuming and ATPgenerating sites in the cell (Zeleznikar et al., 1995; Dzeja et al., 1998). In these chains, a
series of rapidly equilibrating reactions catalyzed by cellular phosphotransferases provide the driving force
for highenergy phosphoryl flux (Wallimann et al., 1992; Saks et al., 1994; Dzeja et al., 1998). According to
this mechanism, incoming ligands at one end of the system ‘‘push’’ adjacent ligands, thereby triggering a
propagation of disequilibrium through an entire cluster of enzymes catalyzing rapid equilibration among
substrates. In this type of system, ligands do not move the entire length of the pathway, as molecules arriving
at the distal sites of this sequence represent the equivalent rather than the specific molecule generated at the
Mitochondria-nucleus energetic communication 6.3 647
origination site. This would provide directionality to the metabolic system and contribute to the efficiency
and accuracy of energetic signaling (Carrasco et al., 2001, Abraham et al., 2002; Dzeja and Terzic, 2003;
Hodgson et al., 2003). The occurrence of ligand conduction apparently requires more structured and
organized systems (Dzeja et al., 1998; Pomes and Roux, 2002), such as enzymatic clusters or molecular wires
(Wegmann et al., 1992; Wild et al., 1997), while reactiondiffusion and metabolic wave propagation can take
place also in a dispersed soluble system such as cellular extracts (Mair and Muller, 1996). Thus, the ligand
conduction mechanism contrasts with the traditional diffusion theory and also with the ‘‘metabolite
channeling’’ concept by operating independently of cytosolic ligand concentrations and without the
movement of a specific ligand through the entire length of the pathway (Dzeja et al., 1998).
It was determined that the effective substrate transfer (conduction), independent of bulk concentration,
occurs when enzymes are spaced apart less than 10 nm (Fossel and Hoefeler, 1987). Using this data and the
relationship between the total number of unidirectional phosphotransfers, determined by
(KingsleyHickman et al., 1987), and the net phosphoryl flux, determined by the
Olabeling technique
(Pucar et al., 2001, 2002), it can be calculated that the average length of intracellular phosphoryl conduction
pathways ranges from 0.5 to 1.0 mm (Dzeja et al., 1998). This length roughly corresponds to the average
distance between the centers of mitochondria and myofibrils. Another feature, underscoring thermody-
namic efficiency, is that enzymatic ligand conduction systems are capable of operating with minimal or no
concentration gradients (Dzeja et al., 1998; Dzeja and Terzic, 2003). This could explain why changes in
cellular adenine nucleotide concentrations are most often not observed even with marked increases in
metabolic flux (Balaban, 1990; Saks et al., 1994).
Intracellular energetic and metabolic signal communication can employ simultaneously several differ-
ent mechanisms depending on the cell type and specific compartment, structural organization, and
topological arrangement of enzymatic networks (Dzeja and Terzic, 2003). While the spatial heterogeneity
and directionality of enzymecatalyzed process is not essential in wellmixed conditions in vitro, this becomes
a vital entity in highly organized living matter (Harold, 1991), with cluster organization and the high rate of
unidirectional phosphoryl exchange in phosphotransfer systems promoting ligand conduction and signal
communication at cellular distances (Wallimann et al., 1992; Dzeja et al., 1998; Dzeja and Terzic, 2003).
3 Phosphotransfer Reactions in MitochondrialNuclear Energetic
Mitochondrialnuclear intercommunication proceeds at the genomic, metabolic/energetic, and signaling
levels (Poyton and McEwen, 1996; Cyert, 2001; Dawson and Dawson, 2004). Nuclearcoded proteins
regulate mitochondrial morphology, intracellular localization, and functional activity (Bach et al., 2003).
Conversely, mitochondrial proteins and generated signals affect nuclear processes leading to altered gene
expression or cell death through apoptosis (Fulco et al., 2003; Dawson and Dawson, 2004; Templeton and
Moorhead, 2004). With respect to energetic communication, intense nuclear functions including DNA
replication, nucleosome and chromatin remodeling, gene transcription, and transport of macromolecules
inside the nucleus and across the nuclear envelope require efficient energy supply, yet the nucleus is
secluded from major cellular ATP generation sites such as mitochondria (Mattaj and Englmeier, 1998;
Dzeja et al., 2002; Ohba et al., 2004). The nuclear ATP pool is compartmentalized (Rapaport, 1980), and the
ATP level in the nucleus depends on the intensity of energyconsuming processes (Gajewski et al., 2003).
Organized enzymatic complexes of nucleotidemetabolizing and phosphotransfer enzymes are involved in
maintaining nuclear dNTP ratios and their channeling into the DNA replication machinery (Mathews,
1985). Although the nuclear compartment contains glycolytic enzymes, the entry point for highenergy
phosphoryls into the glycolytic pathway catalyzed by hexokinase usually is localized at the mitochondrial
site (Ottaway and Mowbray, 1977; Gerbitz et al., 1996; Cesar and Wilson, 1998). This suggests that
glycolytic energy transfer shuttles between mitochondria and nucleus (Dzeja et al., 2004).
Beside hexokinase, the mitochondrial outer membrane and intermembrane space harbor several
phosphotransfer enzymes, which participate in the energetic communication between ATPconsuming pro-
cesses in the cytosol and oxidative phosphorylation in mitochondria (Wyss et al., 1992; Gerbitz et al., 1996;
648 6.3 Mitochondria-nucleus energetic communication
Laterveer et al., 1996; Dzeja et al., 2004). With condensed mitochondrial structures and a narrow inter-
membrane/intracristal space, creatine kinase and adenylate kinase appear necessary in conducting the ADP
stimulatory signal through the adenine nucleotide translocator to matrix ATPsynthases (Gellerich et al.,
1994; Saks et al., 1994; Laterveer et al., 1996; Dzeja and Terzic, 2003). Disruption of the adenylate kinase
gene impedes ATP export and mitochondriacytosolic communication (Bandlow et al., 1988). Inactivation
of adenylate kinase by gene replacement disrupts adenine nucleotide homeostasis and reduces cell viability
(Counago and Shamoo, 2005). Deletion of UbCKmit, a mitochondrial creatine kinase isoform, disrupts
neural energetics during seizures, while deletion of ScCKmit has a lesser effect in the heart, merely
compromising the ability to maintain normal highenergy phosphate levels (Kekelidze et al., 2001; Spindler
et al., 2002). In this regard, in brain mitochondria, adenylate kinase, which could be of cytosolic origin
(AK1 or AK5), is less active and the compensatory potential consequently lower than in the heart (Walker
and Dow, 1982; Wustmann et al., 1987). NDPK (ATP þNDPADP þNTP) present in the mitochondrial
intermembrane space also facilitates the reception of cytosolic nucleoside diphosphatebased signals and
provides a link between ATP generation and energy distribution to synthetic GTP, UTP, and CTP
requiring processes (Gerbitz et al., 1996; Dzeja et al., 2002). Similarly hexokinase, bound to the outer
membrane of mitochondria, directs highenergy phosphoryls through the glycolytic phosphotransfer
network in response to cellular energetic signals (Cesar and Wilson, 1998; Dzeja et al., 2004). Thus,
functional interaction and complementation of creatine kinase, adenylate kinase, and NDPK phospho-
transfer relays in the intermembrane/intracristal space along with porinbound hexokinase provide a
mechanism for the integrated response of mitochondrial oxidative phosphorylation to increased cellular
energy demand (Saks et al., 1994; Roberts et al., 1997; Dzeja et al., 1999b; Dzeja and Terzic, 2003).
Creatine kinase and adenylate kinase isoforms, depending on the developmental or functional state, are
found in the nucleus or bound to the nuclear envelope (Criss, 1970; Manos and Bryan, 1993; Chen et al.,
1995). Recently, a novel nuclear adenylate kinase isoform, AK6, has been characterized (Ren et al., 2005).
Also, a membranebound AK1bisoform, which has been implicated in p53dependent cellcycle arrest
(Collavin et al., 1999), has been found associated with the nuclear envelope (Janssen et al., 2004). Adenylate
kinase isoforms in the brain may further contribute to neuronal maturation and regeneration (Inouye et al.
1998; Yoneda et al., 1998). Glycolytic enzymes are markedly elevated in nuclei of regenerating cells,
suggesting increased nuclear energetic needs (Ottaway and Mowbray, 1977). Recently, it was demonstrated
that mitochondrial ATP production is required to support energyconsuming processes at the nuclear
envelope, while glycolysis alone was insufficient to perform such a function (Dzeja et al., 2002). Although
mitochondrial clustering around the nucleus reduces the distance of energy transfer, oxidative phosphory-
lation and simple nucleotide diffusion are inefficient to meet energy requirements for nucleocytoplasmic
communication. Adenylate kinase phosphotransfer was identified to direct transmission of highenergy
phosphoryls from mitochondria to the nucleus, maintaining the optimal nucleotide ratios required for
active nuclear transport (Dzeja et al., 2002) (>Figure 6.3-2). Moreover, adenylate kinase coupled with
NDPK secures phosphoryl transfer between ATP and GTP, as both nucleoside triphosphates are necessary
for active nuclear transport (PerezTerzic et al., 2001; Dzeja and Terzic, 2003). A mechanistic basis for
thermodynamically efficient coupling of cell energetics with nuclear pore function lies in the unique
property of adenylate kinase catalysis, which transfers both band gphosphoryls of ATP, doubling the
energetic potential of ATP as an energycarrying molecule (Dzeja et al., 1985, 1999b). Inhibition of nuclear
transport by disruption of the adenylate kinase relay can be rescued through upregulation of alternative
phosphotransfer pathways, such as the creatine kinase system, which regulates both adenine and guanine
nucleotide ratios (Wallimann et al., 1992; Dzeja et al., 2002). Indeed, creatine kinase is bound to the nuclear
membrane and present in the nucleus, providing an energy transfer shuttle capability (Manos and Bryan,
1993; Chen et al., 1995).
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 phos-
photransfer in directing cellular energy flow (Ottaway and Mowbray, 1977; Manos and Bryan, 1993; Dzeja
and Terzic, 2003). Thus, phosphotransfer reactions are essential in providing energy for nuclear processes
spatially separated from mitochondrial sites of energy transduction and regulate exchange of molecules and
information between the cytosol and nucleus.
Mitochondria-nucleus energetic communication 6.3 649
In this regard, NDPKphosphotransfer deficient cells have highly biased nucleoside triphosphate pools,
including marked elevations of CTP and dCTP, and a strong mutator phenotype (Bernard et al., 2000).
Imbalance in cellular nucleotide ratios results in increased genetic error frequency (Bebenek et al., 1992),
with NDPK, a product of the tumor suppressor gene Nm23, mutations affecting the processing of genetic
information (Lacombe et al., 2000). Adenylate kinase in the nucleus is responsible for conversion of dADP
to dATP, while creatine kinase can phosphorylate and convert deoxynucleotide diphosphates (dNDPs) into
dNTP and facilitate DNA mismatch repair, an energyrequiring process (Mathews, 1985; Glazer et al.,
1987). Thus, interactions between phosphotransfer enzymes in the nucleus secure proper nucleotide ratios
and the fidelity of processing genetic information.
Glycolytic substrates, both in wild type and mtDNA mutant cells, are able to maintain adequate
ATP supplies in all compartments including the nucleus (Gajewski et al., 2003). Conversely, with the
mitochondrial substrate pyruvate, ATP levels collapse in all compartments of mutant cells with nonfunc-
tional mitochondria. It is suggested that depletion of nuclear ATP plays an important role in disease
pathogenesis in conditions of mitochondrial dysfunction (Gajewski et al., 2003). In wildtype cells, normal
levels of ATP can be maintained with pyruvate in the cytosol and in the subplasma membrane region, but
are reduced in the nucleus. The severe decrease in nuclear ATP content under conditions of compromised
cytosolic glycolytic phosphotransfer implies that other phosphotransfer systems in this type of cells are not
.Figure 6.3-2
Adenylate kinase energy transfer shuttle facilitates energetic communication between mitochondria and
nucleus. Conerted action of mitochondrial (AK2) and cytosolic (AK1) adenylate kinases provide a mechanism
for transfer and utilization of two high-energy phosphoryls (i.e., band g) in one ATP molecule. AK1 coupled
with nucleoside disphosphate kinase (NDPK) at the nuclear envelope secures phosphory1 transfer between ATP
and GTP, as both nucleoside triphosphates are necessary for active nuclear transport. Depending on cell type,
developmental stage and physiological conditions parallel creatine kinase, and glycolytic phosphotransfer
systems (>Figure 6.3-1) can also contribute to mitochondria–nucleus energetic communication
650 6.3 Mitochondria-nucleus energetic communication
sufficiently active to provide ATP and to sustain proper nucleotide ratios in the nuclear compartment. It
also may suggest that coordinated action between several phosphotransfer relays is required to sustain
efficient nuclear energetics. In this regard, the presence of glucose and basal glycolytic phosphotransfer is
usually necessary for mitochondrial substrate signaling to plasma membrane metabolic sensors such as
channels implicated in induction of hormone secretion (Tarasov et al., 2004).
Beside ATP requirements, the nucleus possesses several metabolic sensors which are regulated by
nuclear AMP/ATP and NAD
/NADH ratios (Fjeld et al., 2003; McGee et al., 2003). Nuclear translocation
of the metabolic sensor AMPK mediates exerciseinduced gene expression, regulates phosphorylation and
acetylation of nuclear transport factors affecting their activity, and is critical for hypoxiainducible factor1
transcriptional activity (Lee et al., 2003; McGee et al., 2003; Wang et al., 2004). Silent information regulator
Sir2 is an active NAD
dependent deacetylase critical in transcription silencing and in linking chromatin
function with cellular metabolic networks (Denu, 2003; Blander and Guarente, 2004). Another transcrip-
tional corepressor CtBP has been identified as a nuclear redox sensor mediating nuclear NAD
effects on cell differentiation, development, and transformation (Fjeld et al., 2003). Thus, emerging data on
the energy supply to nuclear processes and metabolic signaling have advanced our understanding of
metabolic requirements and energetic costs of processing and distributing genetic information.
4 PhosphotransferMediated Metabolic Signaling
Metabolic signaling cascades are essential in vital cellular processes integrating gene expression, metabo-
lism, and response to stress, with their deficit associated with diseases under the wide umbrella of the
‘‘metabolic syndrome’’ (Carrasco et al., 2001; Hardie, 2003; Hodgson et al., 2003; Carling, 2004; Tokunaga
et al., 2004; Wang et al., 2004). Understanding the principles governing the integration and synchronization
of metabolic sensors with cellular metabolism is important for regulation of cellular energetic and ionic
homeostasis as well as for hormonal balance and food intake (Dzeja and Terzic, 1998; Carling, 2004;
Minami et al., 2004; Tarasov et al., 2004). Phosphotransfer reactions have emerged as principal signal
generators and relays coupling cellular metabolism and metabolic sensors (Dzeja and Terzic, 1998, 2003;
Hardie, 2003). In particular, adenylate kinasegenerated AMP and AMPK are integral to metabolic
signaling, balancing cellular ATP production and utilization priorities and increasing cell tolerance to stress
(Hardie, 2003; Xing et al., 2003; Frederich et al., 2005). Moreover, the adenylate kinase–AMP–AMPK
pathway integrates complex mTOR, TSC2, LKB1, 1433, and K
channelsignaling cascades, required in
the regulation of vital cellular functions (Carrasco et al., 2001; Carling, 2004; Mak and Yeung, 2004; Rubio
et al., 2004; Selivanov et al., 2004; Tokunaga et al., 2004).
The microenvironment of the prototypic metabolic sensor, the K
channel, harbors several phospho-
transfer enzymes, including adenylate, creatine, and pyruvate kinases, as well as other glycolytic enzymes
that are able to transfer phosphoryls between ATP and ADP in the absence of major changes in cytosolic
levels of adenine nucleotides (Weiss and Lamp, 1987; Dzeja and Terzic, 1998; Carrasco et al., 2001;
Abraham et al., 2002; Crawford et al., 2002; Hodgson et al., 2003; Alekseev et al., 2005). These phospho-
transfer reactions are governed by the metabolic status of a cell, and their phosphotransfer rates closely
correlate with K
channel activity (Zingman et al., 2001). Thus, through delivery and removal of adenine
nucleotides at the channel site, phosphotransfer reactions regulate the dynamics of ATP and ADP exchange
in the immediate vicinity of the channel, and thereby the probability of K
channel opening (Zingman
et al., 2001; Selivanov et al., 2004; Alekseev et al., 2005). In this way, coordinated phosphotransfer reactions
could provide a transduction mechanism coupling cellular metabolic signals with K
functions such as hormone secretion, membrane electrical activity, brain glucose sensing, regulation of
vasculature tone and cerebral circulation as well as protection against metabolic stress (Dzeja and Terzic,
1998; Zingman et al., 2002a; Gumina et al., 2003; Kane et al., 2004; Minami et al., 2004; Tarasov et al., 2004).
While regimented K
channel activity regulates membrane electrical events and associated cellular
functions (Zingman et al., 2002b; Liu et al., 2004; Minami et al., 2004), unregulated channel opening can
precede loss of membrane excitability, excessive vasodilatation, and consequently cardiac and brain
functional arrest (Weiss and Lamp, 1987; Englert et al., 2003). Therefore, systems regulating K
Mitochondria-nucleus energetic communication 6.3 651
activity in response to functional and metabolic changes and preventing uncontrolled channel gating
during metabolic disturbances are warranted (Dzeja and Terzic, 1998; Hodgson et al., 2003). In this regard,
knockout of the creatine kinase MCK gene shifts signal delivery to K
channels through the glycolytic
system (Dzeja et al., 2004), generating a phenotype with increased electrical vulnerability to disturbances in
glucose metabolism (Abraham et al., 2002). Adenylate kinase, which phosphotransfer flux along with AMP
concentration markedly increases under stress, contributes to the response of K
channels to metabolic
challenge (Carrasco et al., 2001; Pucar et al., 2004). Adenylate kinase associates with the K
complex, anchoring cellular phosphotransfer network and facilitating delivery of mitochondrial stress
signals to the submembrane environment. Deletion of the cytosolic adenylate kinase gene (AK1) compro-
mises nucleotide exchange at the channel site and impedes communication between mitochondria and
channels, rendering cellular metabolic sensing defective (Carrasco et al., 2001). Conversely, over-
expression of adenylate kinase results in excessive activation of K
channels (Brochiero et al., 2001). Also,
complementation of membranebound AK1bactivity in neuroblastoma cells, in the presence of appropri-
ate levels of ATP and AMP, promotes opening of the K
channel (Janssen et al., 2004). In neurons,
opening of K
channels reduces the frequency of action potentials, thereby serving a protective function
(Yamada et al., 2001). Existence of synaptic plasma membraneassociated adenylate kinase activity has been
reported earlier for rat and human brains (Nagy et al., 1989; Janssen et al., 2004). In this regard, both
creatine kinase and glycolytic phosphotransfers suppress adenylate kinasemediated nucleotide exchange
(Olson et al., 1996; Dzeja et al., 1998) and maintain K
channel in a predominantly closed state (Weiss
and Lamp, 1987; Abraham et al., 2002). Thus, complementation between creatine kinase, adenylate kinase,
and glycolytic systems provides a mechanistic basis for metabolic sensor function in response to alterations
in intracellular phosphotransfer fluxes (Dzeja and Terzic, 1998; Carrasco et al., 2001; Abraham et al., 2002).
Adenylate kinase is ubiquitously present in all cell types and its activity surpasses by several folds an
apparent need for adenine nucleotide synthesis de novo, one of the classical functions of this enzyme
(Noda, 1973). Adenylate kinase family includes several isoforms (AK1–AK7) with distinct tissue distribu-
tion and subcellular localization (Tanabe et al., 1993; Ruan et al., 2002; Janssen et al., 2004). In the presence
of adenylate kinase, small changes in the balance between ATP and ADP translate into relative large changes
in the concentration of AMP, so that enzymes and metabolic sensors, such as AMPK, that are affected by
AMP can respond with high sensitivity and fidelity to stress signals (Dzeja et al., 1998; Hardie, 2003; Pucar
et al., 2004). Phosporyllabeling experiments indicate that in intact muscle metabolically active ADP and
AMP concentrations are much higher than those obtained from enzyme equilibrium calculations, reflecting
rapid exchange of nucleotides between the free and bound states (Dzeja et al., 1998; Barany and Tombe,
2004). This may involve the mechanism of ‘‘kinetic entrapment’’ and distribution of a large percentage of
the cytosolic ADP and AMP among reversible nucleotidebinding/consuming reactions, which would
continue to function as the metabolically active pool participating in enzymatic relays for metabolic signals
(Dzeja et al., 1998; Dzeja and Terzic, 2003). In this regard, metabolic dynamics and the number of signaling
molecules in the microenvironment (‘‘sensing zone’’) of metabolic sensor rather than static bulk AMP
concentration would determine AMPK activation, similarly to the role of cAMP and cGMP fluxes in
regulation of their specific targets (Dawis et al., 1988). This could explain why sometimes AMPK activation
does not correlate with calculated intracellular AMP levels (Frederich et al., 2005). Future development of
fluorescent reporters sensing intracellular free ADP and AMP concentrations would greatly facilitate our
understanding of cellular energetic signaling.
An increase in intracellular AMP stimulates glycolysis and glycogenolysis due to activation of PFK and
phosphorylase b, respectively (Ottaway and Mowbray, 1977). Through positive and negative nucleotide
feedback interactions, adenylate kinase is a principal component in generating glycolytic oscillations and
maintaining the dynamics of cellular nucleotide exchange (Welch, 1977; Mair and Muller, 1996; Dzeja et al.,
1998). Recent evidence further implicates AMP signaling in metabolic regulation through AMPK and other
AMPsensitive cellular components (Carrasco et al., 2001; Hardie, 2003; Pucar et al., 2004). Indeed, AMP
signaling affects mitochondrial biogenesis and respiration, increasing the muscle energetic capacity (Zong
et al., 2002; Tokunaga et al., 2004; Dzeja and Terzic, 2005). Moreover, AMPK associates with glycogen
particles and could be a target for AMP to inhibit glycogen synthesis and/or activate glycogenolysis/
glycolysis by diverting glucose6phosphate into ATPproducing pathways (Polekhina et al., 2003). Beside
652 6.3 Mitochondria-nucleus energetic communication
AMP, AMPKmediated PFK activation contributes to stimulation of heart glycolysis during ischemia
(Marsin et al., 2000; Xing et al., 2003). Thus, stressinduced changes in adenylate kinase and creatine kinase
equilibriums trigger AMP!AMPK, K
and other signaling cascades, producing adaptive responses in the
metabolic and ion channel systems (>Figure 6.3-3).
Upon hypoxic stress, production of phosphocreatine in mitochondria is compromised due to unfavor-
able thermodynamic and kinetic conditions, leading to depletion of cytosolic energy stores (Wallimann
et al., 1992; Dzeja et al., 2000; Saks et al., 2004). Accordingly, creatine kinasecatalyzed phosphotransfer,
measured by
P NMR in the direction of creatine phosphate production, is reduced under
hypoxic challenge (Pucar et al., 2004). Concomitantly, adenylate kinasecatalyzed
Olabeling of bADP
and bATP is increased, resulting in doubling of adenylate kinase flux. Such activation of adenylate kinase
can protect heart muscle under hypoxia by regenerating ATP, providing a transfer mechanism for ATP
between production and consumption sites, and ultimately initiating AMP and adenosine signaling
(>Figure 6.3-3) (Dzeja et al., 1999b; Pucar et al., 2000, 2002, 2004). Indeed, adenylate kinase remains
active in its ATP regenerating and transferring role as long as ADP is available and the enzyme is not
inhibited by a buildup of AMP (Noda, 1973; Savabi, 1994). In addition, adenylate kinase serves a distinct
metabolic signaling role by translating small alterations in the ATP and ADP balance into large changes in
AMP levels (Dzeja et al., 1998; Dzeja and Terzic, 2003). In this way, adenylate kinase phosphotransfer
communicates metabolic signals to K
channels, AMPK, and adenosine receptors—metabolic sensors
implicated in stress adaptation and cardioprotection (Carrasco et al., 2001; Hardie, 2003; Picher and
Boucher, 2003).
P NMR analysis indicates that a hypoxiainduced increase in AMP phos-
phorylation (ATP þAMP2ADP) would amplify metabolic signals by providing two molecules of ADP
for each ATP removed from ATPsensitive cellular components (Dzeja and Terzic, 1998; Pucar et al., 2004).
Thus, redistribution of flux between adenylate kinase and creatine kinase phosphotransfer, observed under
hypoxic challenge, contributes to a reduction in the bioenergetic deficit and initiates signaling pathways
that promote cellular protection (Pucar et al., 2001, 2004).
.Figure 6.3-3
Interaction of the adenylate kinase (AK), creatine kinase (CK), and glycolytic phosphotransfer system in stress
induced energetic and metabolic signaling triggers protective response. Metabolic or functional stress results
in the fall of ATP/ADP and creatine phosphate/creatine ratios, which increase AK flux resulting in AMP
production and high AMP/ATP ratio. This triggers activation of stress response energetic pathways (increase
utilization of ATP band gphosphoryls) and signaling cascades such as AMPactivated protein kinase (AMPK),
ATPsensitive potassium channel (KATP), and glycolysis/glycogenolysis. Recently discovered AMPreceptors,
along with AMP!adenosine signaling, could contribute to the increased blood flow and tissue oxygen
delivery. Parallel to AMP, Mg
signaling, originating from the MgATP
complex during ATP consumption
and governed by the AK equilibrium, could activate Mg
dependent protein kinases/phosphatases and
dehydrogenases, promoting signal transduction and mitochondrial substrate oxidation
Mitochondria-nucleus energetic communication 6.3 653
The interrelationship between adenylate kinase and creatine kinase is mediated not only by adenine
nucleotide substrates but also by AMPK. Indeed, AMPK activated by adenylate kinasegenerated AMP
phosphorylates and modulates the activity of creatine kinase (Ponticos et al., 1998). AMPK is an energy
sensing enzyme strongly activated during muscle contraction and metabolic stress due to acute decreases in
ATP/ADP and phosphocreatine/creatine ratios (Hardie, 2003; Carling, 2004). In this regard, chronic
phosphocreatine depletion during bGPA supplementation increases brain adenylate kinase activity
(Holtzman et al., 1998) and muscle adenylate kinase flux (P. P Dzeja et al., unpublished) accompanied
by AMPK activation associated with increased cytochrome ccontent and muscle mitochondrial density
(Bergeron et al., 2001). These data demonstrate that, by sensing the energy status of the muscle cell, the
adenylate kinase, creatine kinase, and AMPK signaling triad is a critical regulator involved in the initiation
of mitochondrial biogenesis, thereby increasing the energytransducing capacity of the cell (Zong et al.,
2002). In this regard, glycolytic phosphotransfer and separate glycolytic enzymes, such as GAPDH and
glucokinase/hexokinase, have specific signaling roles beyond their metabolic function in regulating gene
expression and protecting against oxidative stress or apoptotic stimuliinduced cell death (Tatton et al.,
2000; Pastorino and Hoek, 2003).
Thus, phosphotransfermediated integration and synchronization of metabolic sensors with the
dynamics of cellular metabolism is critical for regulation of genetic, energetic, electrical, and signal
transduction processes that determine cell viability and functional activity. Moreover, more and more
evidence is emerging about the direct relationship between defects in metabolic signaling and disease
processes, such as heart failure, diabetes, obesity, cancer, and neurodegeneration.
5 Phosphotransfer Networks in Processing and Integrating
Cellular Information
As discussed above, energeticand metabolicsignaling roles render adenylate kinase and creatine kinase as
important components of cellular physiology determining the fidelity of metabolic response and functional
perfection. Yet several lines of evidence suggest that intracellular and paracellular phosphotransfer networks
may have functions beyond metabolic signaling, energy supply, and distribution, such as in the integration
of cellular information, computation, and memory processing.
Deletion of brain BCK or UbCKmit isoforms indicate that creatine kinase phosphotransfer is fundamental
to processes that involve exploration and habituation, spatial learning, and acoustic startle reflex (Jost et al., 2002;
Streijger et al., 2004). Mice lacking both brain creatine kinase isoforms have reduced body weight, and
demonstrate severely impaired spatial learning, lower nestbuilding activity, and diminished acoustic startle
reflex response (Streijger et al., 2005). Creatine deficiency in humans is associated with movement disorders,
mental retardation, severe language delay, autisticlike behavior, and electroencephalographic abnormalities
(Stockler et al., 1994; Bianchi et al., 2000; Leuzzi, 2002; Schuze et al., 2003). This occurs in spite of normal
brain ATP levels and other metabolic parameters (Bianchi et al., 2000). A novel Xlinked mental retardation
syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the
creatine transporter gene (Rosenberg et al., 2004). The hallmarks of the disorder are mental retardation, learning
disabilities, expressive speech and language delay, epilepsy, developmental delay, and autistic behavior (Salomons
et al., 2003). In humans, genetic adenylate kinase deficiency or losses of adenylate kinase from the brain after
surgery are associated with compromised intellectual function (Aberg et al., 1982; Toren et al., 1994). Similarly,
disturbances in glycolytic phosphotransfer system are associated with deficient memory formation and retrieval
(Hoyer, 2003).
Coupled nearequilibrium enzymatic networks have the ability to provide a precise control similar to a
‘‘digital’’ type of regulation, such that each ATP conversion to ADP, P
, and H
will be signaled to an
equivalent stoichiometry of ADP, P
, and H
transformation to ATP (Saks et al., 1994; Dzeja et al., 2000;
Neumann et al., 2003). It was suggested that information can be encoded in the dynamic behavior of a
chemical oscillating system by forcing the system to follow a desired trajectory (Dolnik and Bollt, 1998). As
such, conversion of 2 ADP to ATP plus AMP and vice versa by adenylate kinase reaction will output signals
to ATP, AMP, and ADPsensitive cellular components inducing oscillatory behavior of metabolic,
654 6.3 Mitochondria-nucleus energetic communication
electrical, and signaltransducing systems (Welch, 1977; Mair and Muller, 1996; Dzeja and Terzic, 2003). It
was noted that the adenylate kinase reaction and factors regulating it contribute significantly to the solution
of the informationcoding algorithm in living cells (Kremen, 1982). Also, analogies have been drawn
between the computational aspects of information processing and the enzymatic events of cellular metabo-
lism (Welch, 1996). In line with this is the notion that information processing proceeds through the tightly
organized networks, that information flows freely and independently yet patterned, so that the necessary
contact and transactions are made quickly and efficiently (Laughlin, 2001).
While nucleotide pool output follows laws of thermodynamics and kinetics, it is regulated primarily by
informational requirements. In processes requiring information supply, such as nucleic acid and protein
synthesis, errorreducing mechanisms are necessary. According to Shannon (1948), the fraction of errors
introduced by noise during message transmission can be reduced only at the expense of additional
information supply. Also, as noted by Welch (1996), diffusion of molecules by itself is a dissipative
phenomenon. Thus, when metabolic processes take place in bulk solution, there is a considerable energy
cost to the cell in the spatiotemporal conveyance of coherent biochemical information. For efficient
coupling of energy and metabolic signal sources with molecular motors and metabolic sensors and,
therefore, for ‘‘activitycausal’’ information flow, a specific spatial organization of enzymatic components
is required in order to increase the kinetic efficiency and to minimize the heatexchange during energy and
signal transduction (McClare, 1971; Dzeja and Terzic, 2003). In protein synthesis, for example, very high
relative amounts of ATP and GTP and coupled phosphotransfer reactions are required to enhance the
translation fidelity (Kremen, 1982). The same is true for DNA synthesis and transcription, where high local
pools of dNTP maintained by phosphotransfer reactions are necessary (Mathews, 1985). Imbalance in
nuclear nucleotide ratios results in increased genetic error frequency (Bebenek et al., 1992; Lu et al., 1996).
Thus, for efficient cellular information transfer organized enzymatic pathways are required, which provide
directionality, increase fidelity, and reduce signaling errors.
Adenylate kinase equilibrium governs not only adenine nucleotide species but also free magnesium
) levels within cells (Rose, 1968; Igamberdiev and Kleczkowski, 2001). It was suggested that Mg
released from the MgATP
complex during ATP consumption, could serve as a feedback signal conveying
information regarding alterations in the adenine nucleotide pool to different cellular compartments (Blair,
1970). In this regard, creatine kinase also regulates adenine nucleotide and adenylate kinase equilibriums,
and consequently can shape Mg
signaling (Vincent and Blair, 1970). Conversely, both creatine kinase and
adenylate kinase reactions by itself are highly dependent on Mg
concentration (Noda, 1973; Saks et al.,
1978), changes of which would produce feedback signals tuning the initial response. In this way, nucleotide
based information processing could be complemented with simultaneous Mg
signaling affecting critical
cellular components, ranging from dehydrogenases, DNA polymerases, ion channels, and protein kinases/
phosphatases (Takaya et al., 2000; Politi and Preston, 2003; Schmitz et al., 2003; Yang et al., 2004). Thus,
phosphotransfer networks could serve a function of coding, processing, and transferring cellular information
and, in conjunction with protein kinase/phosphatase cascades and Mg
signaling, be part of the mechanism
facilitating memory storage and retrieval. Indeed, Mg
deficiency disturbs many brain functions (Galland,
1991–92), while Mg
therapy restores and improves cognitive performance (Hoane et al., 2003).
The critical role of adenylate kinase and creatine kinase in information processing stems from several
physiological and pathophysiological observations. It was noted that there is a close linear relationship
between impaired cerebral energy state and brain memory dysfunction (Kjekshus et al., 1980; Aberg et al.,
1982). The disturbance in energy metabolism may have impacts on energyconsuming processes markedly
reducing cognitive reserve (Hoyer et al., 2004). A linear relationship between cerebral phosphocreatine
concentration and memory capacities has been found (Plaschke et al., 2000; Ross and Sachdev, 2004).
Indeed, creatine supplementation has a significant positive effect on both working memory and intelligence
(Rae et al., 2003). In this regard, photic stimulation increases the creatine kinase unidirectional rate in the
visual cortex without significant changes of steadystate concentration of highenergy phosphate com-
pounds, indicating that phosphocreatine turnover is elevated during increased neuronal activity (Chen
et al., 1997). Similarly, photic stimulation increases adenylate kinasemediated ATP bphosphoryl turnover
in photoreceptors (Dawis et al., 1988).
Plabeling studies of adenine nucleotides indicate that adenylate
kinase is active in the brain and that its phosphotransfer rate is activated by drugs improving cerebral
Mitochondria-nucleus energetic communication 6.3 655
circulation and memory dysfunction (Kanig and Hoffmann, 1979). Recently, an important discovery has
been made linking hypothalamic AMPK to regulation of food intake and obesity (Minokoshi et al., 2004).
This protein kinase serving as master metabolic sensor responds to adenylate kinasegenerated AMP, and
plays a critical role in hormonal and nutrientderived anorexigenic and orexigenic signaling (Hardie, 2003;
Minokoshi et al., 2004). Thus, the adenylate kinase/creatine kinase!AMP!AMPKsignaling cascade
represents a new modality in brain functioning and body energy balance.
Glycolytic phosphotransfer network, which acts in parallel to creatine kinase and adenylate kinase
systems (Dzeja et al., 2004), has also important functions in information processing and memory storage
(Hoyer, 2003). Glucose has been found to improve learning and memory in humans and laboratory
animals, but the underlying mechanisms are unknown (Hoyer, 2003; Messier, 2004). Among possible
mechanisms by which peripheral glucose might act on memory storage is activation of glycolytic phospho-
transfer, which has important roles in energetic signal communication and their spatial distribution in cells
with large dimensions such as neurons (Goldbeter and Nicolis, 1976; Dzeja and Terzic, 2003; Dzeja et al., 2004).
Glucose can also affect substratecyclesmediatedbymembranebound glycolytic enzymes (Chaplain, 1979; Weiss
and Lamp, 1987). Associated with these cycles are slow oscillations in membrane potential, which could be
brought about by the cyclic fluctuations of H
ions and ATP/ADP in the immediate vicinity of the
membrane (O’Rourke et al., 1994). Memory facilitation and consolidation under glycolytic modifiers could
also be demonstrated in avoidanceand discriminationlearning trials with honey bees and rats, which
are consistent with the metabolic nature of the slowwave rhythmicity in vertebrate microneurons
(Chaplain, 1979). Another mechanism by which glucose could affect brain cognitive function is related
to the ability of glycolytic phosphotransfer to regulate K
channels (Weiss and Lamp, 1987; Dzeja and
Terzic, 1998). In this regard, glucose effect on memory storage was attenuated and enhanced by pretreatment
with minoxidil and glibenclamide, an opener and inhibitor of K
channel, respectively (RashidyPour,
2001). Thus, enhanced glycolytic phosphotransfer could be linked to ATPsensitive cellular compo-
nents, including membrane ATPases, ion channels, and nuclear factors regulating neuronal activity and
information processing (Dzeja and Terzic, 2003; Hoyer, 2003).
In brain, another phosphotransfer enzyme NDPK and its coding gene, Nm23, have been implicated
to modulate neuronal cell proliferation, differentiation, and neurite outgrowth as well as tumor meta-
stasis (Kim et al., 2002). Its activity is decreased in Alzheimer’s disease and Down’s syndrome (Kim
et al., 2002). NDPKcatalyzed GDP to GTP conversion regulates Gproteinmediated signaling, nuclear
transport, dynamindependent synaptic vesicle recycling, and microtubule assembly–disassembly (Huitorel
et al., 1984; Krishnan et al., 2001; Dzeja et al., 2002; Hippe et al., 2003). New evidence links cytoskeleton
dynamics with synaptic connectivity, information processing, and cognitive function (Tuszynski et al., 1998;
van Galen and Ramakers, 2005). Axons can send a message to the cell body by mechanisms that require a
complex of the microtubule motor dynein and proteins that mediate nuclearcytoplasmic transport (Hanz
et al., 2003). In this regard, recent data indicate that mitochondria stall near synapses when neurons are
activated (providing energy and acquiring information) and increase their movement (transferring infor-
mation) when neurons are silent (Li et al., 2004). Interestingly, mitochondrial positioning in synapses is
enhanced by supplementation of creatine, which facilitates creatine kinase phosphotransfer (Li et al., 2004).
It is plausible that phosphotransfermodulated microtubule networks and associated mitochondrial move-
ments from synapses to the cell body along with nuclear transport could be involved in neurocomputational
processes, information transfer, and memory engram (Hollenbeck, 1996; Tuszynski et al., 1998).
Information processing in the brain takes place not only intracellularly but also extracellularly and
between different types of cells (Wang et al., 2000; Laughlin, 2001; Gjedde, 2002). In brain, ectoadenylate
kinase is an integral part of the synaptosomal ATPmetabolizing enzyme cascade, regulating ATP, AMP, and
adenosine signaling (Nagy et al., 1989; Joseph et al., 2003). In other cell types ectoadenylate kinase provides
a mechanism for propagation of nucleotidebased signals along cellular surface, thus coordinating multiple
receptormediated signaling events (Yegutkin et al., 2002; Picher and Boucher, 2003). Both ATP and
adenosine signaling, manifested in intercellular ATP waves, are critical for normal brain functioning
(Wang et al., 2000; Latini and Pedata, 2001; Newman, 2003). This type of dynamic nucleotidebased
signaling could be linked with extracellular glutamate waves and related signal transduction (Innocenti
et al., 2000). Recently, a specific AMPreceptor has been discovered too (Inbe et al., 2004). In this regard,
656 6.3 Mitochondria-nucleus energetic communication
extracellular AMP can regulate endocytosis and glycolytic activity in different cell types (Westmoreland
et al., 1986; Mazurek et al., 1997). Adenylate kinasecatalyzed generation of AMP and its subsequent
hydrolysis can produce adenosine which is a ubiquitous homeostatic substance released from most cells,
including neurons and glia (Berne, 1980). Once in the extracellular space, adenosine modifies cell func-
tioning by operating Gproteincoupled receptors that can inhibit (A1) or enhance (A2) neuronal commu-
nication. Manipulations of adenosine receptors influence sleep and arousal, cognition and memory,
neuronal damage and degeneration, as well as neuronal maturation (Ribeiro et al., 2002). The popularity
of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce
adenosine transmission in the brain (Fisone et al., 2004). The important consequence of adenosine
antagonism by caffeine is cholinergic stimulation, which leads to improvement of higher cognitive func-
tions, particularly memory (Riedel et al., 1995). In this regard, redistribution in cellular phosphotransfer
flux and in AMP/adenosine signaling during transient cerebral ischemia, as occurring in hypoxic and
‘‘preconditioned’’ hearts (Pucar et al., 2000, 2004), could be a reason for the dysfunctional learning and
memory behavior (Hoyer, 2003; Hoyer et al., 2004).
A new emerging modality in extracellular and intracellular nucleotide signaling and information
processing is cAMP!AMP!adenosine/AMPK pathway sequentially connecting cAMPand AMP
response elements (Jackson et al., 2003). In this pathway cAMP signaling is followed by conversion of
cAMP by phosphodiesterases to AMP that activates the AMPsignaling cascade (Downs et al., 2002). The
role of adenylate kinase in this system is envisioned to propagate AMP metabolic signals along the
membrane surface or within the cytosolic space and nuclear compartment where AMPK resides (Dzeja
et al., 1998; Turnley et al., 1999; Picher and Boucher, 2003; Wang et al., 2004). Consequently, production of
adenosine from AMP by 50nucleotidase could stimulate adenosinergicsignaling pathways (Berne, 1980).
In this regard, both the cAMPresponse element binding protein (CREB), a transcription factor, and
protein kinase C (PKC), are implicated in the formation of longterm memory (AlvarezJaimes et al.,
2005). Moreover, cAMPdependent protein kinase A (PKA)signaling pathway maintains the cytoplasmic
localization of AMPK in glucosegrown cells (Hedbacker et al., 2004). Conversely, AMPK activation is
linked with the reduction in cAMPmediated signaling (Walker et al., 2003). The association of PKC with
phosphotransfer enzymes creatine kinase and glyceraldehyde3phosphate dehydrogenase, and the regula-
tion of creatine kinase activity by PKCmediated phosphorylation (Wallimann et al., 1992; Reiss et al.,
1996), further emphasize the importance of the integrated cellular phosphotransfer network.
Thus, this kind of integration of cyclic nucleotide!nucleotide!nucleoside signaling provides a means
for coordination of diverse signaling events and information flow from one system to another. The signifi-
cance of organized receptormediated and metabolicsignaling networks is growing, and the current challenge
is to separate the effects of cAMP from those produced by AMP (and perhaps the effects of cGMP from GMP)
in the subsequent signal transduction steps (Downs et al., 2002). In this regard, both cAMP and cGMP have
important functions in brain memory processing (Boess et al., 2004) and their signaling cascades are regulated
by cellular energy metabolism through phosphotransfer relays (Dawis et al., 1988; RuizStewart et al., 2004).
6 Concluding Remarks
Phosphotransfer networks provide the cell with mechanisms supporting energetic communication and the
integration and transmission of a vast amount of metabolic information. Interaction and complementation
between creatine kinase, adenylate kinase, and glycolytic phosphotransfers have significant impact on the
efficiencyof energy transformation, transfer, and utilization processes, providing energy supply pathways from
mitochondria to separate cellular compartments such as the nucleus. Phosphotransfer enzymes are critical in
transduction of metabolic signals governing cellular electrical activity, hormone secretion, and response to
stress. Coupling energetic phosphotransfer enzymes with metabolic sensors and phosphoryltransferring
protein kinase cascades comprises a unified intracellular energy signal transduction matrix capable of proces-
sing, delivering, storing, and retrieving cellular information. These integrated dynamic networks have a critical
impact on brain cognitive function and memory processing. Further elucidation of molecular mechanisms
controlling energetic signaling will contribute to a new understanding of metabolic disorders.
Mitochondria-nucleus energetic communication 6.3 657
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... The CK-PCr circuit represents an efficient regulator of energy flux and uses metabolite channeling as a fine-tuning device for local ATP levels (see Chapters 3 and 7). The significance of such a regulated channeling circuit operating at high total PCr and Cr pools lies in its high sensitivity towards ADP that prevents, especially in excitable cells, the accumulation of ADP and, consequently, AMP through the adenylate kinase reaction [75,76], unless severe stress, such as hypoxia or ischemia, is imposed. In the latter case, AMP-activated protein kinase (AMPK) and other AMP-sensitive components would be activated by free AMP, initiating signaling cascades that would turn on compensatory mechanisms for increasing energy supply and reducing energy consumption [77,78]. ...
... Further insights into and key support for the current understanding of metabolic signaling networks in their full complexity have come with the application of new methodologies in investigations of the in vivo kinetics of energy transfer [75][76][77][78][90][91][92][93]. High-energy phosphoryl fluxes through creatine kinase, adenylate kinase, and glycolytic phosphotransfer, captured with 18 O-assisted 31 P-NMR, tightly correlate with the performance of the myocardium under various conditions of stress load (Fig. 11.7) [77,91], implicating phosphotransfer reactions as indispensable routes that direct the flow of high-energy phosphoryls between cellular ATPases and the ATP production machinery in mitochondria. ...
... (AK)-glycolytic systems, whose contribution increases with muscle contraction and in failing hearts [27,[75][76][77][90][91][92][93]. Such a distribution of contributions between CK, AK, and glycolytic systems is based on the assumption of parallel phosphotransfer pathways. ...
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IntroductionCardiac Energetics: The Frank-Starling Law and Its Metabolic AspectsExcitation–Contraction Coupling and Calcium Metabolism Excitation–Contraction CouplingThe Mitochondrial Calcium CycleLength-dependent Activation of Contractile SystemIntegrated Phosphotransfer and Signaling Networks in Regulation of Cellular Energy Homeostasis Evidence for the Role of MtCK in Respiration Regulation in Permeabilized Cells in SituIn Vivo Kinetic EvidenceMathematical Modeling of Metabolic Feedback Regulation“Metabolic Pacing”: Synchronization of Electrical and Mechanical Activities With Energy SupplyMetabolic Channeling Is Needed for Protection of the Cell from Functional Failure, Deleterious Effects of Calcium Overload, and Overproduction of Free RadicalsMolecular System Analysis of Integrated Mechanisms of Regulation of Fatty Acid and Glucose OxidationConcluding Remarks and Future DirectionsReferences Excitation–Contraction CouplingThe Mitochondrial Calcium Cycle Evidence for the Role of MtCK in Respiration Regulation in Permeabilized Cells in SituIn Vivo Kinetic EvidenceMathematical Modeling of Metabolic Feedback Regulation
... This is due to the significant heterogeneity and local restrictions in the diffusion of adenine nucleotides in cells and to the necessity of rapid removal of ADP from the vicinity of Mg-ATPases to avoid their inhibition by the accumulating product MgADP. As is described in many chapters of this book, not only is ATP delivered by diffusion but also intracellular energy transfer is facilitated via networks consisting of phosphoryl group-transferring enzymes such as creatine kinase (CK), adenylate kinase (AK), and glycolytic phosphoryl-transferring enzymes [39,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105]. Most important among them is the creatine kinase system. ...
... Specific mitochondrial CK isoenzymes (MtCK), called ubiquitous (uMtCK) and sarcomeric (sMtCK), are functionally coupled to oxidative phosphorylation and produce PCr from mitochondrial ATP. PCr in turn is used for local regeneration of ATP by the muscle cytoplasmic isoform of CK (M-CK), driving myosin ATPases or ion pump ATPases [87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105]. Recent studies in CKdeficient transgenic animals indicate that energy transfer and communication between ATP-generating and ATP-utilizing sites within a muscle cell do not rely exclusively upon the activity of CK but rather may include a number of additional intracellular phosphotransfer systems such as AK and glycolysis [106][107][108][109][110][111]. ...
... Recent studies in CKdeficient transgenic animals indicate that energy transfer and communication between ATP-generating and ATP-utilizing sites within a muscle cell do not rely exclusively upon the activity of CK but rather may include a number of additional intracellular phosphotransfer systems such as AK and glycolysis [106][107][108][109][110][111]. AKcatalyzed reversible phosphotransfer between ADP, ATP, and AMP molecules may process cellular signals associated with ATP production and utilization [104,105]. Cluster organization and the high rate of unidirectional phosphoryl exchange in phosphotransfer systems promote ligand conduction and signal communication at cellular distances, providing enhanced thermodynamic efficiency. ...
... concentration en ADP en fonction de plusieurs paramètres, comme la capacité d'utilisation de l'ADP par la MMCK, le modèle révèle l'existence du gradient de concentration de l'ADP entre le centre de la myofibrille et la mitochondrie ( Figure 29C). De plus, la propagation de l'information des impulsions d'ADP se réalise par le mécanisme d'acheminement dirigé du ligand (vectorial ligand conduction) en respectant la diminution du gradient de concentration de l'ADP du centre des myofibrilles vers la mitochondrie (Dzeja et Terzic 2005). L'apparition de ce gradient a été expliquée par la restriction à la diffusion des nucléotides adenyliques dans la cellule (du à l'inhomogénéité du milieu intracellulaire) et par l'état de non-équilibre de la réaction de la CK (Vendelin et al. 2000). ...
... L'hypothèse de la navette suppose l'existence de trois phénomènes:Figure 23 représente graphiquement les modifications métaboliques survenues dans le muscle cardiaque (du chien) en ischémie (Gudbjarnason et al. 1970) -la restriction à la diffusion des nucléotides adényliques due à la microcompartimentation intracellulaire, -le couplage fonctionnel entre les enzymes et les transporteurs ayant pour résultat l'acheminement directe des produits et des substrats et, -l'acceptation du fait que les réactions catalysées par la CK soient en état stationnaire loin de l'équilibre. Le circuit de la CK/PCr aide: -d'une part, à surmonter les barrières de diffusion dans la cellule (Abraham et al., Saks et al. 2004, Schlattner et Wallimann 2004, Selivanov et al. 2004, Vendelin et al. 2004b, Wallimann et al. 1992) et à éviter la dissipation de l'énergie due au transport de l'ATP -et, d'autre part, à éviter accumulation de l'ADP (et donc l'inhibition de l'activité des ATPases en ré-phosphorylant l'ADP) et l'accumulation de l'AMP grâce à la réaction de l'AK(Dzeja et Terzic 2005).Les sites de production et d'utilisation de l'énergie sont mis en relation par une série des réactions de la CK hors d'état d'équilibre ayant pour résultat le transfert presque instantané des groupement Pi vers les sites de demande et le signal métabolique de rétrocontrôle (Cr) vers la mitochondrie(Saks et al. 1994, Wallimann et al. 1992. ...
The aim of our work is to study mechanisms of in situ regulation of respiration of permeabilized muscle cells in order to understand the relationship between regulation of oxidative phosphorylation, energy fluxes and structural organization of the cells. We performed complete kinetic analysis of regulation of respiration in situ of permeabilized cardiac myocytes, supplemented with a system which modeling the effects of glycolysis. The mitochondria network structure was studied using confocal microscopy. Mechanisms of regulation of respiration and energy fluxes in vivo are system level properties. They depend on the complexity of cellular organization and intracellular interactions of mitochondria with cytoskeleton, intracellular MgATPases and cytoplasmic glycolytic system and mechanisms of phosphotransfer and feedback regulation via PCr/CK shuttle in the presence of highly selective restriction to the diffusion at the level of the outer mitochondrial membrane. We applied this protocol to study the regulation of mitochondrial respiration in experimental and clinical studies. The investigation of cardiotoxic effect of doxorubicin showed that its mechanism is highly dependent on the loss of MtCK/OxPhos functional coupling. Skeletal muscle dysfunction of patients with chronic obstructive pulmonary disease is characterized by a high affinity of oxidative phosphorylation for free ADP which decreases after endurance training and high affinity of MtCK for creatine which does not change significantly after training.
... Many nuclear processes, including DNA replication and cell cycle events such as mitotic spindle movement, chromosome disjunction, and karyokinesis, also ATP-dependent chromatin remodeling and gene transcription, as well as initiation of developmental and regenerative programming, require robust energy supply (Dzeja and Terzic 2003Folmes et al. 2011aFolmes et al. , b, 2012aMorettini et al. 2008;Rosenfeld et al. 2009). However, the nucleus is separated from the cytosolic energetic system, and energy supply routes to nuclear processes, including cell cycle and cytokinesis machinery, are largely unknown Dzeja and Terzic 2007). In this regard, cells and nuclei of dividing and regenerating cells in tissues are enriched in energetic and phosphotransfer enzymes to support high energy needs of genetic reprogramming and cell division cycle (Dzeja and Terzic 2009;Hand et al. 2009;Noda 1973;Ottaway and Mowbray 1977;Rosenfeld et al. 2009). ...
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The adenylate kinase isoform network is integral to the cellular energetic system and a major player in AMP metabolic signaling circuits. Critical in energy state monitoring and stress response, the dynamic behavior of the adenylate kinase network in governing intracellular, nuclear, and extracellular nucleotide signaling processes has been increasingly revealed. New adenylate kinase mutations have been identified that cause severe human disease phenotypes such as reticular dysgenesis associated with immunodeficiency and sensorineural hearing loss and primary ciliary dyskinesia characteristic of chronic obstructive pulmonary disease. The adenylate kinase family comprises nine major isoforms (AK1–AK9), and several subforms with distinct intracellular localization and kinetic properties designed to support specific cellular processes ranging from muscle contraction, electrical activity, cell motility, unfolded protein response, and mitochondrial/nuclear energetics. Adenylate kinase and AMP signaling is necessary for energetic communication between mitochondria, myofibrils, and the cell nucleus and for metabolic programming facilitating stem cell cardiac differentiation and mitochondrial network formation. Moreover, it was discovered that during cell cycle, the AK1 isoform translocates to the nucleus and associates with the mitotic spindle to provide energy for cell division. Furthermore, deletion of Ak2 gene is embryonically lethal, indicating critical significance of catalyzed phosphotransfer in the crowded mitochondrial intracristae and subcellular spaces for ATP export and intracellular distribution. Taken together, new evidence highlights the importance of the system-wide adenylate kinase isoform network and adenylate kinase-mediated phosphotransfer and AMP signaling in cellular energetics, metabolic sensing, and regulation of nuclear and cell cycle processes which are critical in tissue homeostasis, renewal, and regeneration.
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Comprehensive characterization of disease-related metabolomic phenotypes and drug effects requires monitoring metabolite levels and their turnover rates. Tandem application of stable isotope 18O-assisted 31P NMR and mass spectrometric techniques uniquely allow simultaneous measurements of phosphorus-containing metabolite levels and their dynamics in tissue and blood samples. The 18O labelling procedure is based on incorporation of the 18O atom, provided from H218O, into Pi with each act of ATP hydrolysis and the subsequent distribution of 18O-labeled phosphoryls amongst phosphate-carrying molecules. Essentially, all major phosphometabolites and their turnover rates can be quantified using 18O-assisted 31P NMR spectroscopy and mass spectrometry. This technology permits the simultaneous recording of ATP synthesis and utilization, phosphotransfer fluxes through adenylate kinase, creatine kinase and glycolytic pathways, as well as mitochondrial nucleotide dynamics and glycogen turnover. Another advantage of 18O methodology is that it can measure almost every phosphotransfer and hydrolytic reactions taking place in the cell including the turnover of small pools of signaling molecules, and the dynamics of energetic signal communication. Our studies demonstrate that 18O-assisted 31P NMR/mass spectrometry is a valuable tool for phosphometabolomic and fluxomic profiling of transgenic models of human diseases, providing valuable data which reveals system-wide adaptations in metabolic networks.
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In: Integrated and Organized Cellular Energy Systems. Wiley Encyclopedia of Chemical Biology March 15, pages 366-392 (2009) Bioenergetics as a part of biophysical chemistry and biophysics is a quantitative science that is based on several fundamental theories.The definition of energy itself is given by the first law of thermodynamics, and application of the second law of thermodynamics shows that the living cells can only function as open systems in which internal order (lowentropystate) is maintained by increasing the entropy in surrounding medium (Schrödinger’s principle of negentropy). For this mechanism, exchange of mass is needed that yields metabolism as the sum of catabolism and anabolism.The free-energy changes taking place during metabolic reactions obey rules of chemical thermodynamics, which deals with Gibbs free energy of chemical reactions and with electrochemical potentials. Fo rapplication of these theories to the integrated systems in vivo, complex cellular organization should be accounted for macromolecular crowding, metabolic channeling and functional coupling mechanisms caused by close and tight protein-protein interactions, compartmentation of enzymes, as well as both macrocompartmentation and microcompartmentation of substrates and metabolites in cells should be considered. For integration of these systemc omponents, effective methods of communication, including compartmentalized energy transfer systems, are required. These systems are represented in muscle cells by phosphotransfernetworks, mostly by creatine kinase and adenylate kinase systems. System analysis of these networks shows their central role both in energy transfer and metabolic feedback regulation of mitochondrial function, in regulation of ion fluxes and cellular energetics during increased workload by synchronizing the cellular electrical and mechanical activities with energy supply and substrate oxidation.
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Technological innovations and translation of basic discoveries to clinical practice drive advances in medicine. Today's innovative technologies enable comprehensive screening of the genome, transcriptome, proteome, and metabolome. The detailed knowledge, converged in the integrated "omics" (genomics, transcriptomics, proteomics, and metabolomics), holds an immense potential for understanding mechanism of diseases, facilitating their early diagnostics, selecting personalized therapeutic strategies, and assessing their effectiveness. Metabolomics is the newest "omics" approach aimed to analyze large metabolite pools. The next generation of metabolomic screening requires technologies for high throughput and robust monitoring of metabolite levels and their fluxes. In this regard, stable isotope 18O-based metabolite tagging technology expands quantitative measurements of metabolite levels and turnover rates to all metabolites that include water as a reactant, most notably phosphometabolites. The obtained profiles and turnover rates are sensitive indicators of energy and metabolic imbalances like the ones created by genetic deficiencies, myocardial ischemia, heart failure, neurodegenerative disorders, etc. Here we describe and discuss briefly the potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic.
In 2001 we identified a new inborn error of metabolism caused by a defect in the X‐linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X‐linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X‐linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come fromone metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X‐linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.
K+ channels are transmembrane proteins that are essential for the transmission of nerve impulses. Three articles recently published in Nature attempts to elucidate the ion conduction through K+ channels at the atomic level using complementary approaches. There are seven main sites for ions along the pore axis: one in the pore cavity, closer to the intracellular face of the channel, four in the selectivity filter and two just beyond the external end of the pore. The internal cavity site is fully occupied by a single K+ ion but only half of the remaining six sites are occupied at any one time. The K+ ion in the internal cavity is stabilized by eight molecules of water. The crystal structure and the molecular dynamics free energy simulations concur that two distinct binding sites for K+ ions are present in the extracellular entryway. The ions in the selectivity filter (narrow region of the pore) move in a concerted fashion between two configurations, K+-water-K+-water and water-K+-water-K+-water-K+, until a third ion enters, displacing the ion on the opposite side of the queue. For K+, the energy difference between these two configurations is close to zero implying that the process of ion conduction is limited by diffusion.
This chapter emphasizes the general principles of brain metabolism and the haemodynamic response to neuronal activity. The precise mechanisms responsible for the links between brain energy metabolism and brain work are not well defined. The chapter gives a detailed description of the nature of the metabolic work for information transfer in the brain, which provides an understanding of the link between changes in energy metabolism affecting physiological parameters such as blood flow and neuronal activity. It proceeds with a discussion of biochemical pathways that provide energy for brain work and also discusses the role of astrocytes in the regulation of the metabolic response to neuronal excitation. The chapter attempts to identify an alternative regulator that changes in response to work and influences the rate of energy metabolism.
This chapter describes adenylate kinase and discusses the studies analyzing this enzyme. Adenylate kinase from rabbit muscle was originally purified to a considerable extent by Colowick and Kalckar by taking advantage of its remarkable acid and heat stability. The enzyme is plentiful in tissues where the turnover of energy from adenine nucleotides is great, such as muscle and mitochondria. The ubiquity of adenylate kinase is shown by the variety of materials in which it is found. Adenylate kinase was shown to be present in nuclei isolated from thymus and also in nuclei from mammary adenocarcinoma cells, in lemon leaves, in sweet and sour lemons, in wheat, and in red blood cells. It was purified from cockroach muscle mitochondria. Adenylate kinase has been purified from bovine eye lens and a baker's yeast enzyme has been studied at length. In the slime mold, Physuruin polycephalum, Chin and Bernstein also studied the variation of adenine nucleotide pools with the stage of growth and found that adenosine monophosphate (AMP) concentration did not vary with adenosine diphosphate (ADP) and adenosine triphosphate (ATP), possibly indicating that adenylate kinase was compartmentalized or otherwise not functioning at all the stages of growth.
Water diffusion magnetic resonance imaging (dMRI) allows tissue structure to be probed and imaged on a microscopic scale, providing unique clues to the fine architecture of neural tissues and to changes associated with various physiological and pathological states, such as acute brain ischaemia. Because diffusion is anisotropic in brain white matter, reflecting its organization in bundles of fibres running in parallel, dMRI can also be used to map the orientation in space of the white matter tracks in the brain, opening a new window on brain connectivity and brain maturation studies. This article provides an introduction to the key physical concepts that underlie dMRI, and reviews its potential applications in the neurosciences and associated clinical fields.