Shuttle Systems in Metabolism

Shuttle systems are an integral part of animal metabolism.

The NADH produced outside the mitochondria during glycolysis in the cytosol cannot diffuse through the impermeable inner membrane of mitochondria, where the electron transport chain occurs. Thus, the oxidation of extra-mitochondrial NADH through the ETC faces several problems.

Plants have an external NADH dehydrogenase on the outer surface of the inner membrane of mitochondria that helps with the transfer of electrons from external NADH. However, animal mitochondria lack this external NADH dehydrogenase. Although external NADH can not diffuse across the inner membrane, its reducing equivalents can diffuse through mechanisms known as ‘shuttle systems.

Shuttle Systems

There are two types of shuttle mechanisms in animals- the malate-aspartate shuttle and glycerol phosphate shuttle systems.

Malate Aspartate Shuttle

The malate shuttle occurs in animal tissues such as heart muscles. This shuttle system is important as the inner mitochondrial membrane is impermeable to oxaloacetate acid and NADH. This shuttle system involves two antiporter proteins in the inner mitochondrial membrane.

Glutamate-aspartate transporter (transporter I)
Malate-α-ketoglutarate transporter (transporter II)

Mechanism of Malate Aspartate Shuttle System

In the malate-aspartate shuttle, the electrons from cytosolic NADH are passed to oxaloacetate coming from the Krebs ’ cycle.
Oxaloacetic acid is reduced to form malate with the help of cytosolic malate dehydrogenase.
Malate is transported across the inner mitochondrial membrane with the help of malate-alpha-ketoglutarate, the antiporter.
When malate is transported into the mitochondrial matrix, alpha-ketoglutarate is transported out into the cytosol.
Inside the mitochondria, malate is oxidised into oxaloacetic acid by mitochondrial malate dehydrogenase and releases the electrons to NAD+, which will become NADH.
This NADH enters the ETC to yield ATPs.
At the same time, the oxaloacetate inside the mitochondria is converted into aspartate by the action of mitochondrial aspartate aminotransferase. Here, glutamate supplies the amino radical and transforms itself into alpha-ketoglutarate.
The glutamate-aspartate antiporter transfers glutamate from the cytosol into the mitochondrial matrix while transporting aspartate into the cytosol, where it becomes oxaloacetic acid by cytosolic aspartate aminotransferase.
Thus, in the malate-aspartate shuttle, one antiporter transports malate into the matrix from the cytosol, and the second antiporter transports aspartate from the matrix into the cytosol.

Significance of Malate Aspartate Shuttle

In the malate-aspartate shuttle, the glutamate-aspartate transporter transfers a proton (H*) as well from the cytosol into the matrix. This causes a decrease in the proton motive force across the inner membrane. Therefore, there is not much ATP generation through the oxidation of cytosolic NADH. The resultant ATP generation is three.

Glycerol Phosphate Shuttle

The glycerol phosphate shuttle system is not common in humans. It is particularly seen in tissues of insect flight muscle, brain, brown adipose tissue, white muscle cells, liver cells.

Mechanism of Glycerol Phosphate Shuttle System

In this shuttle system, the electrons are transported through glycerol 3-phosphate into the mitochondria.
Dihydroxyacetone phosphate is reduced to glycerol-3-phosphate using the cytosolic NADH.
Cytosolic glycerol 3-phosphate dehydrogenase oxidizes NADH to NAD+.
Glycerol 3-phosphate, being a small molecule, can readily diffuse across the mitochondrial membrane, where it is oxidised to form dihydroxyacetone phosphate again.
This oxidation reaction is coupled with the reduction of FAD into FADH₂.
FADH₂ enters the ETC and yields 2ATP molecules by transferring the electrons from FAD to ubiquinone and thus into Complex III.
At the same time, dihydroxyacetone phosphate returns to the cytosol.
Once again, dihydroxyacetone phosphate is reduced to glycerol-3-phosphate.
Dihydroxyacetone phosphate escapes into the cytosol, and the shuttling continues.
Glycerol phosphate shuttle does not involve any type of membrane transport systems.

Significance of Glycerol Phosphate Shuttle

The NADH that enters the glucerophosphate shuttle comes from glycolysis. Since FADH₂ enters the ETC at a lower energy level than NADH, there are fewer ATP molecules produced when compared to the malate-aspartate shuttle. However, by transferring electrons from the cytoplasm to the mitochondria, it allows efficient energy production, which is beneficial for tissues with high energy demands, such as skeletal muscle, where it helps ensure a continuous supply of ATP.

References

Jain, V. K. (1974). Fundamentals of Plant Physiology (19th ed.). S. Chand Publishing.
Glycerol phosphate shuttle: STEPS. (n.d.). https://adpcollege.ac.in/online/attendence/classnotes/files/1623927361.pdf
Unknown. (n.d.). Shuttle system in Metabolism. https://adpcollege.ac.in/online/attendence/classnotes/files/1623839204.pdf