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1993
). A central bioenergetic question in muscle cells relates to the mechanism of
PCr synthesis in mitochondria. This question arises because the equilibrium and
kinetic constants of all CK isoforms would favor only the resynthesis of MgATP
from PCr and MgADP (Saks et al.
2010
; Guzun et al.
2009
). Kinetic information
available is in agreement with the role of MM-CK at the sites of local ATP
regeneration in myofibrils and membranes of sarcolemmal and sarcoplasmic retic-
ulum, but this is not the case for PCr synthesis in mitochondria. More insight can be
obtained from the classical problem of cardiac physiology—the metabolic aspect of
the basic Frank-Starling law of the heart (Saks et al.
2006c
,
2012
). Discovered in
1914-1926, the Frank-Starling law states that under physiological conditions
contractile force, cardiac work, and the rate of oxygen consumption increase
manifold with the filling of the left ventricle (Starling and Visscher
1927
). Later
it was found that this occurs without any changes in the ATP and PCr levels
(metabolic stability) and Ca
2+
transients (Neely et al.
1972
; Balaban et al.
1986
).
The latter observation excludes any explanation involving a mechanism of control
of mitochondrial respiration by changes in intracellular Ca
2+
.ACa
2+
-mediated
mechanism may be important only in the case of adrenergic activation of the heart
(Tarasov et al.
2012
; Balaban
2012
). Assuming that ATP, ADP, PCr, and Cr are
related through equilibrium relationships, the observation of metabolic stability was
interpreted to exclude any other explanation of workload dependence of cardiac
oxygen consumption than a mechanism involving the control of mitochondrial
respiration by ADP or Pi only. The popular assumption of CK equilibrium, as in
a mixed bag of enzymes (Wiseman and Kushmerick
1995
), however, is in contra-
diction with the experimental evidence (Saks
2008
; Guzun and Saks
2010
). This
includes recent high-resolution
31
P NMR experiments showing that the major part
of adenine nucleotides, notably ATP in muscle cells, exists associated with
macromolecules and that free ADP may be only transiently present in the cytoplasm
(Nabuurs et al.
2010
,
2013
). We have shown that both high PCr fluxes in the heart
detected by Dzeja and collaborators (Dzeja and Terzic
2003
,
2009
; Dzeja
et al.
1999
; Nemutlu et al.
2012
) and the linear dependence of the rate of oxygen
consumption on cardiac work may be explained by local signaling and metabolic
channeling of adenine nucleotides in nonequilibrium CK reactions (Saks
et al.
2012
; Guzun et al.
2009
; Timohhina et al.
2009
). Actually, CK can catalyze
within the same cell either the forward or the backward reaction depending on in
which microcompartment the enzyme is located and where it functions as part of
different multienzyme complexes.
Mechanisms involving the interaction of mitochondria and CKs with other
cellular structures and multienzyme complexes are central for understanding meta-
bolic stability in the heart. This implies a different perspective in the framework of
systems biology. Figure
11.7a
shows the localization of the tubulin isotype
II
following the pattern of mitochondrial distribution in cardiac cells (Saks et al.
2012
;
Gonzalez-Granillo et al.
2012
; Guzun et al.
2011b
,
2012
). Tubulin
β
II is part of the
heterodimer tubulin that binds to VDAC in MOM, thus modulating the close
probability of this channel specifically so that it is permeated by Cr or PCr but
limited for ATP or ADP (Guzun et al.
2009
; Timohhina et al.
2009
). In cardiac
β
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