How does the yield of ATP from complete oxidation of one molecule of glucose in muscle and brain differ from that in liver, heart, and kidney? What is the underlying reason for this difference?

Glycolysis is the first stage of glucose metabolism. It takes place in the cytoplasm of the cell and does not require oxygen. Glycolysis starts with one molecule of glucose (a six-carbon sugar) and ends with two molecules of pyruvate (a three-carbon compound).

During glycolysis, a total of 4 ATP molecules are produced, but 2 are used up in the process, so the net gain is 2 ATPs. Additionally, glycolysis produces 2 molecules of NADH, which can be used in other stages of metabolism for further ATP production.

Glycolysis is especially important for tissues with high-energy demands, such as muscles and the brain, but the efficiency of ATP yield varies based on the way NADH is shuttled into the mitochondria for further metabolism.

The citric acid cycle, also known as the Krebs cycle or TCA cycle, occurs in the mitochondria. It follows glycolysis and is a crucial part of cellular respiration. The cycle starts with acetyl-CoA, produced from pyruvate through a process called pyruvate decarboxylation.

Acetyl-CoA combines with oxaloacetate to form citrate, which then undergoes several transformations, releasing two molecules of CO₂ and regenerating oxaloacetate.

During the cycle, each acetyl-CoA generates 1 ATP (or GTP), 3 NADH, and 1 FADH₂. Since two molecules of acetyl-CoA are produced from one glucose molecule, the citric acid cycle yields 2 ATP, 6 NADH, and 2 FADH₂ for each glucose that is completely oxidized.

Oxidative phosphorylation is the final stage of cellular respiration and takes place in the inner mitochondrial membrane. Here, the NADH and FADH₂ produced during glycolysis and the citric acid cycle donate electrons to the electron transport chain (ETC).

The ETC consists of a series of protein complexes that transfer electrons through a series of redox reactions. As electrons move down the chain, protons (H⁺ ions) are pumped from the mitochondrial matrix to the intermembrane space, creating a proton gradient.

This gradient drives the synthesis of ATP as protons flow back into the mitochondrial matrix through ATP synthase. Each NADH typically results in the formation of 2.5 ATPs, and each FADH₂ produces 1.5 ATPs. The total ATP yield from oxidative phosphorylation is dependent on how the electrons from cytosolic NADH are transferred into the mitochondria.

The glycerol phosphate shuttle is a mechanism for transferring electrons from NADH produced in glycolysis into the mitochondria, especially in muscle and brain tissues.

Instead of directly transferring the electrons to the mitochondrial NAD⁺, the glycerol phosphate shuttle transfers them to FAD, forming FADH₂. Since FADH₂ enters the electron transport chain at a lower energy level than NADH, it results in the production of fewer ATP molecules.

Specifically, each NADH that donates its electrons via the glycerol phosphate shuttle leads to the generation of approximately 1.5 ATPs rather than the 2.5 ATPS that NADH would typically generate. This difference is a key reason why the ATP yield from glucose oxidation is lower in muscle and brain tissues.

The malate-aspartate shuttle is another mechanism for transferring electrons from cytosolic NADH into the mitochondria, but it is used by liver, heart, and kidney tissues.

Unlike the glycerol phosphate shuttle, this mechanism transfers electrons to NAD⁺ within the mitochondria, forming NADH. The NADH can then enter the electron transport chain and contribute to the generation of around 2.5 ATPs per molecule.

Because the malate-aspartate shuttle allows the high-energy electrons from cytosolic NADH to be transferred to mitochondrial NAD⁺ without loss of energy, the ATP yield from complete oxidation of glucose is typically higher in these tissues—up to 32 ATPs per glucose molecule.