Lecture 21- Energy Generation & Metabolism

What is the main difference in energy yield between oxidative phosphorylation & glycolysis alone?

Oxidative phosphorylation yields more energy than glycolysis alone.

What are carbohydrates in the context of metabolism?

Main sources of energy in metabolism.

Where does glycolysis occur in the cell?

Cytosol of the cell.

What is glycolysis?

Glycolysis is a metabolic pathway that converts glucose into pyruvate.

What role do fats & proteins play in metabolism?

Sources of energy in metabolism.

What is pyruvate?

End product of glycolysis.

What is lactate?

Byproduct of anaerobic metabolism that can be produced from pyruvate.

What happens to ADP during oxidative phosphorylation?

ADP is phosphorylated to form ATP during oxidative phosphorylation.

What is the role of CO2 in metabolism?

Byproduct of metabolism that is released during oxidative phosphorylation.

Where does the Krebs cycle occur in the cell?

Mitochondria of the cell.

What is the Krebs cycle?

Series of biochemical reactions that produce energy in the form of ATP.

What is the main product of oxidative phosphorylation?

ATP

What is the role of coenzyme-2H in metabolism?

Transfer of electrons during oxidative phosphorylation.

What is the role of oxygen in metabolism?

Necessary for oxidative phosphorylation to occur.

What is oxidative phosphorylation?

Process that produces ATP from the energy released by the transfer of electrons from NADH & FADH2 to oxygen in the mitochondria.

What is the end product of oxidative phosphorylation?

water (H2O).

What are the two ways to process nutrients?

Glycolysis & the tricarboxylic acid cycle (also known as the Krebs cycle).

What is the energy yield of glycolysis?

2 ATP molecules.

What is the starting molecule for glycolysis?

Glucose.

Where does oxidative phosphorylation occur in the cell?

Oxidative phosphorylation occurs in the mitochondria of the cell.

What are the products of oxidative phosphorylation?

ATP, water, & carbon dioxide.

What is the role of NADH + H+ in oxidative phosphorylation?

Source of electrons for oxidative phosphorylation.

What is the role of FADH2 in oxidative phosphorylation?

Another source of electrons for oxidative phosphorylation.

What is the tricarboxylic acid cycle?

Series of biochemical reactions that generate energy from the oxidation of acetyl CoA.

Where does the tricarboxylic acid cycle occur in the cell?

Occurs in the mitochondria of the cell.

What is the energy yield of the tricarboxylic acid cycle?

ATP molecules, as well as NADH + H+ & FADH2, which are used in oxidative phosphorylation to produce more ATP.

What is the starting molecule for the tricarboxylic acid cycle?

Acetyl coenzyme A.

What are the products of the tricarboxylic acid cycle?

NADH + H+, FADH2, ATP, carbon dioxide, & water.

How many ATP molecules are produced in total from the processing of glucose through glycolysis, the tricarboxylic acid cycle, & oxidative phosphorylation?

34-38 ATP molecules.

What are the main nutrients consumed & used by the myocardium?

Fatty acids, glucose, lactate, & ketone bodies.

What percentage of the myocardium's energy needs come from fatty acids?

Approximately 60%

What percentage of the myocardium's energy needs come from glucose?

Approximately 27%

What percentage of the myocardium's energy needs come from lactate?

Approximately 10%

What percentage of the myocardium's energy needs come from ketone bodies?

Approximately 2%

What is the role of pyruvate in myocardial metabolism?

Converted into acetyl-CoA, which enters the tricarboxylic acid cycle to produce energy in the form of ATP.

What is the storage capacity of glycogen in the myocardium compared to skeletal muscle?

Equivalent to 1/5 of that in skeletal muscle.

What is the role of phosphorylated creatine in myocardial metabolism?

Serves as a small reserve of phosphate in the myocardium.

Why is the myocardium completely reliant on lipid & glucose supply by the coronary circulation?

The myocardium is unable to synthesise lipids, thus making it completely reliant on lipid & glucose supply by the coronary circulation.

How do the limited nutrient reserves & continuous function of the cardiac pump affect myocardial metabolism?

These features make the myocardium a supply-limited tissue from the metabolic perspective, thus tightly linking nutrient & oxygen supply with cardiac function or dysfunction.

How does the myocardium maintain ATP levels?

Sustained mitochondrial respiration.

What are the O2 & ATP consumption levels of the heart with respect to its mass?

The heart has very high O2 & ATP consumption levels with respect to its mass.

What is the reason for the high O2 & ATP consumption levels of the heart?

The high O2 & ATP consumption levels of the heart are due to a high density of mitochondria in each cardiomyocyte.

What happens to cardiomyocytes when O2 consumption exceeds supply?

When O2 consumption exceeds supply (hypoxia), cardiomyocytes have no other option than breaking down glucose (glycolysis) to produce ATP.

Why is glycolysis insufficient in the mid-to-long term?

Glycolysis is insufficient in the mid-to-long term, which is the metabolic basis for cardiac failure.

What do the red & grey regions in the image represent?

The red regions represent mitochondria, while the grey regions represent sarcomeres.

Why are O2 levels crucial for cardiac metabolism & function?

Heart is highly dependent on O2 supply & consumption.

What are some factors that affect O2 supply in cardiac metabolism?

Myocardial arterial venous oxygen content difference (MAVR)
Diastolic time,
Pump function
Coronary flow
Ventilation
Haemoglobin saturation.

What is MAVR in cardiac metabolism?

Difference in oxygen content between arterial & venous blood in the myocardium.

What is the role of diastolic time in cardiac metabolism?

Filling of the coronary arteries, which can affect O2 supply in the myocardium.

How does pump function affect O2 supply in cardiac metabolism?

Determines the cardiac output, which affects blood flow to the coronary arteries.

What is the role of coronary flow in cardiac metabolism?

Delivering O2 & nutrients to the myocardium.

How does ventilation affect O2 supply in cardiac metabolism?

Affects the oxygenation of arterial blood.

What is the role of haemoglobin saturation in cardiac metabolism?

Delivering O2 to the myocardium.

What are some factors that affect O2 consumption in cardiac metabolism?

Heart rate
Myocardial mass
Contractility
Sympathetic activity
Pre/afterload.

What is the percentage of total O2 consumption at rest that is attributed to the heart?

At rest, the heart is responsible for approximately 10% of total O2 consumption.

Why is the myocardium considered a supply-limited tissue from a metabolic perspective?

It is a terminally vascularized organ where O2 supply depends exclusively upon coronary blood flow, & the cardiac pump must function continuously.

What are the two main processes that the myocardium distributes ATP expenditure between?

Contractile apparatus & maintenance of ion gradients.

What are some sources of fatty acids in the myocardium?

Albumin, chylomicrons, & fatty acid transporters such as CD36 & MCT.

What is the role of glucose in myocardial metabolism?

Source of energy in the myocardium through glycolysis & the tricarboxylic acid cycle.

What is the role of GLUT in myocardial metabolism?

Glucose transporter that helps transport glucose into the myocardial cells.

What is the role of acetyl-CoA in myocardial metabolism?

Intermediate molecule that enters the tricarboxylic acid cycle to produce energy in the form of ATP.

What is the role of the carnitine shuttle in myocardial metabolism?

Transporting fatty acids into the mitochondria for oxidation.

What is the role of the citric acid cycle (Krebs cycle) in myocardial metabolism?

Series of biochemical reactions that generate energy from the oxidation of acetyl-CoA.

What is the energy yield of oxidative phosphorylation compared to glycolysis?

The energy yield of oxidative phosphorylation is 18 times higher than glycolysis.

How does the heart obtain ATP from different energy substrates?

The heart obtains 60-90% of its ATP from lipids through beta-oxidation, while 10-30% comes from the breakdown of glucose through glycolysis.

What are some of the processes that require ATP in the myocardium?

⅔ of ATP is used by the contractile apparatus

⅓ s used to maintain ionic gradients, such as the Na+/K+ ATPase & SERCA pump.

What happens to the myocardium when coronary blood flow is impaired?

Myocardium relies on glycolysis, which consumes most ATP on the maintenance of ionic gradients, thus starving contractile apparatus & further aggravating cardiac pump function

What is the preferred source of ATP in a non-hypoxic, well-perfused heart?

Most of the ATP in a non-hypoxic, well-perfused heart is derived from fatty acid beta-oxidation.

What is the role of myosin ATPase in myocardial metabolism?

Producing force in the myocardium.

What is the role of ion gradients in myocardial metabolism?

Maintaining the proper function of cardiac cells, including the regulation of calcium ions & the Na+/K+ ATPase.

What happens to ATP usage in a failing heart?

Glucose oxidation becomes the dominant source of ATP
More ATP is used for ion homeostasis instead of force production → ↓↓↓ cardiac efficiency.

What are some sources of energy substrates in myocardial metabolism?

Fatty acids, glucose, lactate, & ketone bodies.

What are some transporters involved in myocardial metabolism?

GLUT for glucose, MCT for lactate, & CD36 for fatty acids.

What is the role of glycolysis in myocardial metabolism?

Source of energy for the myocardium, especially during times of hypoxia or low nutrient perfusion.

What is the role of beta-oxidation in myocardial metabolism?

Process of breaking down fatty acids for energy production in the myocardium.

What is the tricarboxylic acid (TCA) cycle?

Series of biochemical reactions that generate energy from the oxidation of acetyl-CoA.

What is oxidative phosphorylation in myocardial metabolism?

Process of producing ATP through the electron transport chain in the mitochondria.

What are some ATP-dependent processes in the myocardium?

Contractile element (myosin ATPase), calcium regulation (SERCA2 & sarcolemmal Ca2+ ATPase), & ion homeostasis (Na+/K+ ATPase).

What is myosin ATPase?

Enzyme that hydrolyzes ATP to produce force in the myocardium.

What happens in a hypoxic, poorly perfused (ischaemic) heart?

Supply of oxygen & nutrients is reduced → ↑↑↑ in lactate production & a ↓↓↓ in fatty acid beta-oxidation.

Why is glycolysis less efficient than oxidative phosphorylation?

Produces fewer ATP molecules per glucose molecule.

What happens to myosin ATPase in a hypoxic, poorly perfused heart?

More ATP is used to maintain ion homeostasis rather than force production by myosin ATPase → ↓↓↓ cardiac efficiency.

What is the role of lactate in myocardial metabolism?

Source of energy in hypoxic conditions where fatty acid beta-oxidation is impaired. However, high levels of lactate can also be detrimental to cardiac function.

How does ↓↓↓ fatty acid beta-oxidation affect myocardial efficiency?

A shift towards glycolysis, which is less efficient in producing ATP.

As a result, the heart is less efficient in producing force & more ATP is used to maintain ion homeostasis, leading to ↓↓↓ cardiac efficiency.

What is the electron transport chain?

Series of protein complexes in the inner mitochondrial membrane that transfer electrons & protons to generate a proton gradient for ATP production

How does impaired energy generation & metabolism in the heart affect its function?

Lead to impaired contractile function, which can manifest as decreased cardiac output or impaired relaxation (diastolic dysfunction) → lead to changes in the electrical activity of the heart, which can manifest as arrhythmias.

How can arrhythmias be an early sign of heart failure?

Occur as a result of impaired energy generation & metabolism, & can be an early sign of heart failure before changes in the pulse. So the electrical signalling fails before the anatomical pumping

What is the main pathway for ATP generation in myocardial metabolism under hypoxia/ischaemia?

Glycolysis

What is glycogen in the context of myocardial metabolism?

Storage form of glucose that can be broken down into glucose molecules for use in glycolysis.

What is ppp in the context of myocardial metabolism?

Pentose phosphate pathway, which is an alternative pathway for glucose metabolism that generates NADPH & ribose-5-phosphate.

What is NADPH in the context of myocardial metabolism?

Coenzyme that is involved in the production of fatty acids & the removal of ROS (reactive oxygen species) in the cell.

What is ROS in the context of myocardial metabolism?

Reactive oxygen species, which are harmful molecules that can cause cellular damage & contribute to various diseases.

What is FADH in the context of myocardial metabolism?

Coenzyme that is involved in the electron transport chain, which generates ATP through oxidative phosphorylation.

What is NADH in the context of myocardial metabolism?

NADH is a coenzyme that is involved in the electron transport chain, which generates ATP through oxidative phosphorylation.

What is ATP synthase in the context of myocardial metabolism?

ATP synthase is an enzyme that synthesises ATP from ADP & inorganic phosphate during oxidative phosphorylation.

What is glutamate in the context of myocardial metabolism?

Amino acid that is involved in the TCA cycle & can generate FADH2 for use in oxidative phosphorylation.

How does hypoxia affect myocardial metabolism?

Reduces the availability of oxygen for oxidative phosphorylation, leading to a shift towards glycolysis for ATP production.

What is the energy yield of metabolism under hypoxia compared to aerobic metabolism?

Only 2 ATP molecules per glucose molecule, whereas aerobic metabolism yields 36 ATP molecules per glucose molecule.

What is the relationship between NAD+ & NADH in myocardial metabolism?

NAD+ is the oxidised form of the coenzyme, while NADH is the reduced form.
The balance between the two is important for energy production in the cell.

What is the role of sympathetic activation in myocardial glycolysis?

Simulates myocardial glycolysis.