Cori Cycle/lactic acid cycle/glucose lactate cycle(Gluconeogenesis from Lactate)

Cori Cycle

(Gluconeogenesis from Lactate)

Also known as lactic acid cycle or glucose lactate cycle.
The cycle involving the synthesis of glucose in liver from the skeletal muscle lactate and the reuse of glucose thus synthesized by the muscle for energy purpose is known as Cori cycle.
It is a process in which glucose is converted to Lactate in the muscle and in the liver this lactate is re-converted to glucose.
Lactate produced by active skeletal muscle is a major precursor for gluconeogenesis.

Mechanism of Cori Cycle:

Under anaerobic conditions, pyruvate is reduced to lactate by lactate dehydrogenase (LDH)
In an actively contracting muscle, pyruvate is reduced to lactic acid which may tend to accumulate in the muscle.
Lactate is a dead end in glycolysis, since it must be reconverted to pyruvate for its further metabolism.
The very purpose of lactate production is to regenerate NADH so that glycolysis proceeds uninterrupted in skeletal muscle.
Lactate or pyruvate produced in the muscle cannot be utilized for the synthesis of glucose due to the absence of the key enzymes of gluconeogenesis (glucose 6-phosphatase and fructose 1,6-bisphosphatase).
To prevent lactate accumulation, body utilizes cori cycle.
The plasma membrane is freely permeable to lactate. So lactic acid from muscle diffuses into the blood.
Lactate is carried from the skeletal muscle through blood and handed over to liver, where it is oxidized to pyruvate.
Pyruvate, so produced, is converted to glucose by gluconeogenesis, Regenerated glucose can enter into blood and then transported to the skeletal muscle.
The cycle involving the synthesis of glucose in liver from the skeletal muscle lactate and the
reuse of glucose thus synthesized by the muscle for energy purpose is known as Cori cycle
From a biochemical point of view, the Cori cycle links gluconeogenesis with anaerobic glycolysis

Energy cost of the Cori cycle

The Cori cycle results in a net consumption of 4 ATP.
The gluconeogenic leg of the cycle consumes 2 GTP and 4 ATP per molecule of glucose synthesized, that is, 6 ATP.
The ATP-consuming reactions are catalyzed by:

pyruvate carboxylase: 1 ATP;

phosphoenolpyruvate carboxykinase: 1 GTP;

glyceraldehyde 3-phosphate dehydrogenase : 1 ATP.

Since two molecules of lactate are required for the synthesis of one molecule of glucose, the net cost is 2 x 3 = 6 high energy bonds per molecule of glucose.
Conversely, the glycolytic part of the cycle produces only 2 ATP per molecule of glucose.
Therefore, more energy is required to produce glucose from lactate than that obtained by anaerobic glycolysis in extrahepatic tissues.
This explains why the Cori cycle cannot be sustained indefinitely.

Importance of Cori cycle:

The continuous breakdown and resynthesis of glucose, feature of the Cori cycle, might seem like a waste of energy.
Indeed, this cycle allows the effective functioning of many extrahepatic cells at the expense of the liver and partly of the renal cortex. Examples are:

Red blood cells

These cells, lacking a nucleus, ribosomes, and mitochondria, are smaller than most other cells.
Their small size allows them to pass through tiny capillaries.
The lack of mitochondria makes them completely dependent on anaerobic glycolysis for ATP production.
Then, the lactate is partly disposed of by the liver and renal cortex.

Skeletal muscle

Its cells, and particularly fast-twitch fibers contracting under low oxygen conditions, such as during intense exercise, produce much lactate.
the rate of ATP production by anaerobic glycolysis is greater than that produced by the complete oxidation of glucose.
Therefore, to meet the energy requirements of contracting muscle, anaerobic glycolysis is an effective means of ATP production.
But this could lead to an intracellular accumulation of lactate, and a consequent reduction in intracellular pH.
Cori cycle, in the liver dispose of a large part of the muscle lactate, thereby allowing the muscle to use ATP for the contraction.

During trauma, sepsis, burns, or after major surgery, an intense cell proliferation occurs in the wound, that is a hypoxic tissue, and in bone marrow. This, in turn, results in greater production of lactate, an increase in the flux through the Cori cycle and an increase in ATP consumption in the liver.
A similar condition seems to occur also in cancer patients with progressive weight loss.
The Cori cycle is also important during overnight fasting and starvation.

References:

Online Biochemistry Notes