Flashcards in L49 – Metabolic features of cardiac tissue Deck (54):
What is used for 60-70% Myocardial ATP production under normal aerobic conditions?
Non-esterified fatty acids (NEFA)
2 sources of Non-esterified fatty acids (NEFA)?
Diet (fatty acids, glucose)
Mobilize stored forms (triacylglycerides in
adipocytes, glycogen in liver and muscle)
How does dietary lipid reach myocardia? Start with dietary lipid in micelles
Dietary lipid (triglycerides (TG)) >
micelles > in small intestine (duodenum):
pancreatic lipase cleaves TG into fatty acids (FA) + glycerol > enter intestinal cell>
reconstitute 2-monoglycerides + FA into TG > coat with phospholipids / lipoprotein > chylomicrons enter blood via
lymphatics > heart
How does stored glycogen in liver become mobilized?
In liver: glucose > glycerol-3-phosphate + FA-CoA > TG > coat with lipoprotein to form VLDL > blood
How does stored TAG in adipose tissue become mobilized?
Hormone (e.g. glucagon) activate G protein > adenylate cyclas > cAMP > Protein Kinase A > activate lipase > TG becomes DAG > release FA + glycerol
What 2 ways is FA + glycerol released into blood?
How does circulating TG enter skeletal/ cardiac muscle?
1. breakdown TG into FA + glycerol
2. FA enter muscle through FA translocase
fatty acid translocase (FAT)/CD36 has a preference for which type of Fatty acid?
Long chain fatty acid (LCFA)
What are the 2 enzymes on outer mitochondrial membrane for FA transport?
Carnitine palmitoyl-transferase 1 (CPT1)
Write the reaction catalysed by acyl-CoA synthase.
Fatty acid binding protein (FABP) + CoA + ATP > FABP + fatty acyl-CoA + AMP + PPi
Where does the reaction catalysed by acyl-CoA synthase occur?
Outside of outer mitochondrial membrane
Fatty acyl CoA enters intermembrane space of mitochondria. What is the reaction there?
fatty acyl- CoA + carnitine > fatty acylcarnitine + CoA
Catalyzed by Carnitine Palmitoyl-transferase 1 (CPT1)
Which enzyme is important in regulating whether FA can enter intermembrane space?
Carnitine Palmitoyl-transferase 1 (CPT1)
What is the role of Carnitine?
Carnitine takes over CoA in carrying FA from intermembrane space through inner membrane to mitochondrial matrix
Which two enzymes are found on inner mitochondrial membrane for FA transport?
Carnitine acylcarnitine translocase
Carnitine Palmitoyl-transferase II (CPT2)
What is the reaction of Carnitine Palmitoyl-transferase II (CPT2)? Where does it occur?
Fatty acylcartinine + CoA > fatty acyl CoA + cartinine
Where is fatty acyl CoA found in the membranes of mitchondria?
Outside mitochondria, in intermembrane space (before being converted to fatty acylcartinine and in matrix
Where is fatty acylcartinine found in the membranes of mitochondria?
In intermembrane space and matrix (before being converted to fatty acyl CoA)
What happens to the cartinine in matrix after being detached from fatty acylcartinine?
Carried by cartinine acylcartinine translocase from matrix to intermembrane space
What happens to fatty acyl CoA inside the matrix ?
undergoes β-oxidation to produce:
1. FADH2, NADH
What is the fate of the acetyl CoA made from the β-oxidation of fatty acyl CoA in mitochondria?
Acetyl-CoA (2-C) combines with
oxaloacetate to form citrate > enter TCA cycle > metabolized into
CO2, H2O, NADH, FADH2
What is the fate of the FADH2, NADH made from the β-oxidation of fatty acyl CoA in mitochondria?
Enter electron transport chain > pump H+
into intermembrane space > H+ goes down concentration gradient to drive ATP synthase > produce ATP
What accounts for the minority 30% of Myocardial ATP production under normal aerobic conditions?
What is the fate of glucose used in ATP production in cardiomyocyte?
Enter cardiomyocyte via channel (e.g. GLUT 4) > glycolysis by hexokinase > form pyruvate
> pyruvate catalyzed by PDH to form Acetyl- CoA > TCA cycle > ETC > ATP made
What is the least used metabolite in Myocardial ATP production under normal aerobic conditions?
Lactate, ketone body
How is Fatty acid / glucose chosen for use in cardiomyocyte?
Use one means inhibiting use of the other
When utilization of Fatty acid in mitochondria is high, what is the action of NADH made in B-oxidation?
NADH made in B-oxidation activates PDH KINASE > phosphorylate and inhibit PDH > pyruvate from glucose inhibited to form acetyl CoA
When utilization of Fatty acid in mitochondria is high, what is the action of citrate made in TAC cycle after B-oxidation?
Citrate leaves mitochondria by SLC25A1 channel > inhibits phosphofructokinase 1 in cytosol
(PFK1 = rate-limiting enzyme in glycolysis)
Which two enzymes are inhibited when FA utilization is high in cardiomyocyte? Which enzyme is activated?
PFK1 - inhibit by citrate
PDH - inhibit by activated PDH kinase (by NADH)
MCD/Malonyl-CoA decarboxylase is activated
When glucose utilization is high, Which enzyme is stimulated?
PDH is stimulated (e.g. by L-carnitine)
What is the role of MCD/Malonyl-CoA decarboxylase?
Transport LCFA into mitochondria when FA utilization is high
When glucose utilization is high, which enzyme is inhibited to stop FA oxidation?
Glucose > pyruvate > Acetyl CoA
Acetyl CoA A inhibits 3-ketoacyl thiolase (= last step in B-oxidation)
What are the 2 sources of Acetyl-CoA in cytosol when glucose utilization is high in cardiomyocyte?
1) Citrate leave mitochondria through SLC25A1 transporter > cleaved by ATP-citrate lyase (ACL) into acetyl CoA
2) Acetyl CoA in mitochondria > mitochondrial ACT > acetylcarnitine > cytosolic ACT > acetyl CoA
When glucose utilization is high, what enzyme is used to turn Acetyl CoA into malonyl CoA?
acetyl CoA carboxylase
What is the role of malonyl CoA in the heart when glucose utilization is high?
In heart > inhibit Carnitine palmitoyl-transferase 1 (CPT1) @ outer mitochondrial membrane > less FA enter mitochondria
What is the role of malonyl CoA in the liver when glucose utilization is high?
In liver: malonyl CoA > FA synthase > palmitate > FACoA
What is the enzyme for converting malonyl CoA back into Acetyl CoA?
malonyl CoA decarboxylase (MCD)
If O2 is in short supply, which metabolism pathway is stimulated and which is inhibited?
stimulate acetyl-CoA from glycolysis and inhibit β-oxidation
During oxygen deprivation, which metabolites accumulate? What metabolism is inhibited?
B-oxidation is inhibited > accumulate fatty acyl CoA, fatty acylcarnitine
Accumulation of acetyl CoA and NADH > inhibit PDH > stop glucose metabolism too
During Hypoxia / mild ischaemia, which pathway is stimulated to make ATP?
Accumulation of ADP, AMP stimulate PFK > glycolysis
Also trigger glycogenolysis
How does severe ischaemia cause cell death via ATP?
No O2 > accumulate lactate and H+ > inhibit PFK & glyceraldehyde 3-phosphate dehydrogenase > stop glycolysis > no ATP > irreversible cell injury and death
During aerobic reperfusion, what is generated that reacts with polyunsaturated membrane lipids (FA chains) to cause cellular injury?
Oxygen-derived free radicals
made from One-electron reduction of oxygen, electrons not taken up properly by antioxidants
What are the effects of oxygen derived free radicals to cause cellular injury?
Lipid peroxidation > degrade FA > increase membrane permeability > swelling
Damage mitochondria + mDNA
Damage DNA, SER, RER
Why does inhibition of FA oxidation excerbate the cellular injury caused by oxygen derived free radicals?
Stop B-oxidation > accumulate FA intermediates > inhibit glucose metabolism > uncouple ETC from oxidative metabolism
What free radicals are formed during aerobic reperfusion?
hydrogen peroxide (H2O2)
hydroxyl radical (OH')
Which metabolism pathway is better for ATP production after an episode of MI?
Inhibit B-oxidation after episode of MI
What drugs are used to increase glucose utilization after an episode of MI?
Oxfenicine, (etomoxir, perhexiline)
T3 (triiodothyronine = thyroid hormone)\
What is the function of Oxfenicine?
Increase glucose utilization, inhibit CPT1
Increase lactate and pyruvate production
What is the function of MCD inhibitor ?
Increase Malonyl CoA content > inhibit CPT1 > stop FA entering mitochondria
Stimulate PDH, thus glucose utilization
What is the function of T3?
improve coupling of glycolysis to glucose
What is the function of glucose-insulin-potassium (G-I-K)?
help transport glucose into cell
What is the function of Infuse intralipid-heparin?
Displace LPL from heparan sulfate peptidoglycan (HSPG) on endothelial surface
> FA held by albumin but cannot enter tissues
What drug used to treat hypertension has a similar action to Oxfenicine and MCD inhibitor?
B-blockers inhibit CTP1 and 2 on mitochondria membranes