Biology Reference
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[MgATP], mM
[MgATP], mM
a
b
0 , 0
2,0
4,0
6,0
8,0
10,0
12,0
180
160
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100
80
60
40
20
0
0,0
0,2
0,4
0,6
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1,0
1,2
1,4
[MgATP], mM
Fig. 11.9 The energy flux control in permeabilized cardiomyocytes: creatine stimulation of
mitochondrial respiration .(a) Flux control coefficients for MtCK, adenine nucleotide translocase
(ANT), ATP synthasome (ATPsyn), respiratory complexes I (C I), III (C III), IV (C IV), and
inorganic phosphate carrier (PiC). The right panel shows the sum of flux control coefficients.
Reproduced from (Tepp et al. 2011 ) with permission. (b) The role of endogenous ADP produced in
MgATPase reactions at different concentrations of MgATP in the regulation of mitochondrial
respiration in permeabilized cardiomyocytes under different conditions: ( square )—without ADP
trapping system (PEP-PK) and in the absence of Cr; ( filled circle )—without PEP-PK system but in
the presence of 20 mM Cr (i.e., activated MtCK); ( triangle )—in the presence of both trapping
system for free ADP and 20 mM Cr. Reproduced from (Timohhina et al. 2009 ) with permission
Taken together this information allows explaining the linear relationship
existing between oxygen consumption and cardiac work by local metabolic feed-
back signaling within ICUEs (Saks et al. 2010 , 2012 ; Aliev et al. 2012 ) (Fig. 11.10 ).
Direct flux determination and mathematical modeling show that not more than
10 % of free energy is transported out of mitochondria by ATP flux needed to
equilibrate the information-carrying flux of ADP into mitochondria. According to
this model, ADP released from actomyosin cross-bridges stimulates the local
MM-CK reaction in the myofibrillar space within ICEUs while at the same time
forms a concentration gradient towards mitochondria (Fig. 11.10a-c ) (Dos Santos
et al. 2000 ; Aliev et al. 2012 ; Aliev and Saks 1997 ; Vendelin et al. 2000 ). The
amplitude of displacement of MM-CK from equilibrium, as well as cyclic changes
in ADP, is proportionally increased with workload (Fig. 11.10b, c ). The
rephosphorylation of ADP in the MM-CK reaction increases locally the Cr/PCr
ratio that is transferred towards MtCK via the CK/PCr shuttle. Regulation of VDAC
permeability by
II tubulin is a key element mediating the linear response of
mitochondrial respiration to local signaling within ICEUs. When MOM is perme-
able, as in isolated mitochondria, modulation of respiration is impossible because of
saturating ADP concentrations used under these conditions. The latter exceeds
manifold the apparent affinity of oxidative phosphorylation for
β
free ADP
( K m app ADP
¼
μ
μ
M)
(Fig. 11.11a ). On the contrary, when ADP diffusion is restricted at the level of
7.9
1.6
M),
even in diastolic phase
(about 40
 
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