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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
140
120
100
80
60
40
20
0
0,0
0,2
0,4
0,6
0,8
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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