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myofibril
A P
Ca 2+
T-tubule
3Na +
Randle cycle
SR
Ca 2+
FFA
CD36
acyl-CoA
CPT1
-
+
acyl-carnitine
AMP
+
AMPK
ADP
CK
CPT2
ATP
PCr
Cr
ADP
ase
malonyl-CoA
acyl-CoA
ATP
Ca 2+
+ ?
-
NADH
ACC
b -FAO
+
CRU
Cr
CRT
MCD
ETF
+
TpC
acetyl-CoA
acetyl-CoA
PDH
Kinase signaling
circuits
phosphotransfer
cycles
Krebs
cycle
mtCK
+
+
ATP
ADP
Cr
PCr
GLUT4
PFK2
Pyr
GLU
NADH
ATP
CK
VDAC
ase
ATP
NAD+
NAD+
dehydro-
genases
NADH
Pi
ADP
ATP
H
+
ADP
Y
OAA
mal
mal
OAA
+
tubulin
AK1
AK2
mal/asp shuttle
½O 2 +2H +
H 2 O
CK
AMP
Pi
sarco-
lemma
H +
cytc
H +
FADH 2
Cr
PCr
Na +
NADH
Ca 2+
H +
CO 2
QH 2
e
CoQ
K +
Cr
O 2
e
ATP
CK
Ca 2+
PCr
H +
ADP
ATP
mitochondrion
ase
SR
O 2
3Na +
2K +
T-tubule
O 2
+
-
metabolite flux
signaling flux
acvang
inhibing
enzymes
transporters and channels
Fig. 11.4 Metabolic cycles and signaling networks in cardiomyocyte—Intracellular Energy Units
(iEU). Free fatty acids (FFA, upper left ) are taken up by a family of plasma membrane proteins
(fatty acid transporter protein, FATP1, fatty acid translocase, CD36), and in the cytoplasm FAs are
associated with fatty acid binding protein (FABP). FFAs are esterified to acyl-CoA via fatty acyl-
CoA synthetase. The resulting acyl-CoA is then transported into mitochondria via carnitine
palmitoyltransferase I (CPT and CPT II). Once inside, acyl-CoA becomes a substrate for the
β
-oxidation produces 1 mole-
cule of NADH, 1 molecule of FADH 2 , and 1 molecule of AcCoA. AcCoA enters the Krebs cycle,
where it is further oxidized to CO 2 with the concomitant generation of 3 molecules of NADH,
1 molecule of FADH2 and 1 molecule of ATP. Glucose (GLU) is taken up by glucose transporter-4
(GLUT-4, at the left middle ) and enters the Embden-Meyerhof pathway, which converts glucose
into 2 molecules of pyruvate (PYR). As a result of these reactions, 2 net ATP and 2 NADH are
produced. NADH is transferred into mitochondria via the malate-aspartate shuttle. OAA, oxalo-
acetate; Glut, glutamate; α KG, α -ketoglutarate; ASP, aspartate; MAL, malate. Most of the
metabolic energy derived from glucose can come from the entry of pyruvate into the Krebs
cycle and oxidative phosphorylation via AcCoA. NADH and FADH2 issued from both metabolic
pathways are oxidized in the respiratory chain. Mitochondrial creatine kinase (mtCK) catalyzes
the direct transphosphorylation of intramitochondrial ATP and cytosolic creatine (Cr) into ADP
and phosphocreatine (PCr). ADP enters the matrix space to stimulate oxidative phosphorylation,
while PCr is transferred via the cytosolic Cr/PCr shuttle to be used in the functional coupling
between CK and ATPases (acto-myosin ATPase and ion pumps, black circles ). Feedback regula-
tion of substrate supply occurs in the following way: the glucose-fatty acid (Randle) cycle: if
glucose and FFAs are both present, FFAs inhibit the transport of glucose across the plasma
membrane, and acyl-CoA oxidation increases the mitochondrial ratios of AcCoA/CoA and of
NADH/NAD+ which inhibit the pyruvate dehydrogenase (PDH) complex. Citrate from increased
production in the Krebs cycle can inhibit phosphofructokinase (PFK). These changes would slow
down oxidation of glucose and pyruvate (PYR) and increase glucose-6-phosphate (G6P), which
-oxidation pathway, resulting in AcCoA production. Each round of
β
 
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