Shuttle Pathways or Systems
(Transport of reducing equivalents)
- The inner mitochondrial membrane is impermeable to NADH.
- NADH produced in the cytosol cannot directly enter the mitochondria.
- NADH produced in the glycolysis is extramitochondrial, whereas the electron transport chain, where NADH has to be oxidized to NAD+ is in the mitochondrion.
- NADH produced in cytosol transfer the reducing equivalents through the mitochondrial membrane via substrate pairs, linked by suitable dehydrogenases by shuttle systems.
- It is important that the specific dehydrogenases which act as “shuttle” be present on both sides of the mitochondrial membrane.
- Two such shuttle systems are there:
1. Glycerophosphate shuttle
2. Malate-aspartate shuttle
Glycerophosphate shuttle:
- This shuttle system is not much common to be used in humans. It is present in insect flight muscle and in white muscle.
- This alternative means of moving reducing equivalents from the cytosol to the respiratory chain operates in skeletal muscle and the brain.
- It delivers the reducing equivalents from NADH through FAD in
glycerol 3-phosphate dehydrogenase to ubiquinone and thus into Complex III, not Complex I - Cytosolic glycerol 3-phosphate dehydrogenase oxidizes NADH to NAD+.
- The reducing equivalents are transported through glycerol 3-phosphate into the mitochondria.
- An isozyme of Glycerol 3-phosphate dehydrogenase—present on the outer surface of the inner mitochondrial membrane— reduces FAD to FADH2.
- Dihydroxyacetone phosphate escapes into the cytosol and the shuttling continues.
- FADH2 gets oxidized via ETC to generate 2 ATP.
- Note that this shuttle does not involve membrane transport systems.
Malate-aspartate shuttle (Malate shuttle):
- This shuttle system is more common and universal.
- This shuttle for transporting reducing equivalents from cytosolic NADH into the mitochondrial matrix is used in the liver, kidney, and heart.
- Reduced NADH + H+ is reformed in the mitochondrion, which is oxidized in respiratory chain produces 3 ATP.
- The system is rather a little complex as OAA is impermeable to mitochondrial membrane; whereas malate, aspartate, glutamate, and α-ketoglutarate are permeable to the mitochondrial membrane.
- So OAA reformed in mitochondrion has to be transaminated to form aspartate.
- In the cytosol again OAA is regenerated by transamination.
- This shuttle involves membrane transport systems.
- In the cytosol, oxaloacetate accepts the reducing equivalents (NADH) and becomes malate.
- Malate then enters mitochondria where it is oxidized by mitochondrial malate dehydrogenase.
- In this reaction, NADH and oxaloacetate are regenerated.
- NADH gets oxidized via electron transport chain and 3 ATP are
produced. - This is in contrast to glycerolphosphate shuttle where only 2 ATP are
produced. - In the mitochondria, oxaloacetate participates in transamination reaction with glutamate to produce aspartate and α-ketoglutarate.
- The aspartate enters the cytosol and transaminates with α-ketoglutarate to give oxaloacetate and glutamate.
Steps of Malate-aspartate shuttle:
- NADH in the cytosol enters the intermembrane space through openings in the outer membrane (porins), then passes two reducing equivalents to oxaloacetate, producing malate. 2
- Malate crosses the inner membrane via the malate–α-ketoglutarate transporter.
- In the matrix, malate passes two reducing equivalents to NAD+, and the resulting NADH is oxidized by the respiratory chain; the oxaloacetate formed from
malate cannot pass directly into the cytosol. - Oxaloacetate is first transaminated to aspartate, and
- Aspartate can leave via the glutamate-aspartate transporter.
- Oxaloacetate is regenerated in the cytosol, completing the cycle, and glutamate produced in the same reaction enters the matrix via the glutamate-aspartate transporter.
Note:
- When body utilises α-glycero-P-shuttle, net ATP produced by glycolysis—TCA cycle per molecule glucose oxidised will be 36 ATP (2 ATP less) and NOT 38 ATP.
- Use of Malate shuttle will form 38 ATP
Shuttle pathways and tissues
- Liver, kidney, and heart utilize malate-aspartate shuttle, and yield 3 ATP per mole of NADH.
- Skeletal muscle and the brain utilize glycerol-phosphate shuttle and liberate 2 ATP from NADH.
References:
- Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
- John W. Pelley, Edward F. Goljan (2011). Biochemistry. Third edition. Philadelphia: USA.
- Smith, C. M., Marks, A. D., Lieberman, M. A., Marks, D. B., & Marks, D. B. (2005). Marks’ basic medical biochemistry: A clinical approach. Philadelphia: Lippincott Williams & Wilkins.
- https://en.wikipedia.org/wiki/Malate-aspartate_shuttle
- https://en.wikipedia.org/wiki/Glycerol_phosphate_shuttle
Leave a Reply