Cellular respiration is how cells extract energy from glucose, beginning with glycolysis. Glycolysis, the initial stage, converts a single glucose molecule into two molecules of pyruvate. Glycolysis exclusively generates the high-energy electron carrier Nicotinamide Adenine Dinucleotide (NADH). It does not produce Flavin Adenine Dinucleotide (FADH\(_{2}\)), which is generated in a later stage of cellular metabolism.
Understanding the Glycolysis Pathway
Glycolysis is a ten-step metabolic pathway occurring in the cytosol, the substance filling the cell. It begins with a six-carbon glucose molecule and ends with two three-carbon pyruvate molecules, regardless of oxygen presence. The process has an energy-requiring phase and an energy-releasing phase. Two molecules of ATP are consumed initially, and four are produced later, resulting in a net gain of two ATP molecules per glucose molecule.
NADH production occurs during the sixth step of glycolysis, catalyzed by the enzyme glyceraldehyde-3-phosphate dehydrogenase. This enzyme oxidizes the three-carbon molecule glyceraldehyde-3-phosphate, removing high-energy electrons and a proton. Nicotinamide Adenine Dinucleotide (NAD\(^{+}\)) accepts these electrons and the proton, becoming reduced to NADH.
Since one molecule of glucose splits into two three-carbon molecules, a total of two NADH molecules are generated from a single glucose molecule. The continuation of this metabolic process depends on the continuous recycling of NADH back to NAD\(^{+}\). The enzyme is structurally tailored to use NAD\(^{+}\) as its electron acceptor, which is why FAD is not used.
Where FADH2 is Generated
The generation of FADH\(_{2}\) takes place in the mitochondrial matrix during the Citric Acid Cycle (Krebs Cycle). This cycle further processes the remnants of glucose after conversion to acetyl-CoA, releasing stored energy. FADH\(_{2}\) production occurs at a single step within this cycle.
FADH\(_{2}\) is produced during the conversion of succinate to fumarate, catalyzed by the enzyme succinate dehydrogenase. This enzyme is unique because it is embedded in the inner mitochondrial membrane, unlike most Citric Acid Cycle enzymes. It uses Flavin Adenine Dinucleotide (FAD) as a prosthetic group, a molecule tightly bound to the enzyme structure.
FAD is the electron acceptor due to the chemical nature of the succinate-to-fumarate conversion. This reaction removes electrons and protons from succinate, but its chemical energy is lower than reactions where NAD\(^{+}\) is reduced. FAD is a stronger oxidizing agent than NAD\(^{+}\), allowing it to accept electrons from a less energetic starting molecule like succinate.
The Ultimate Purpose of NADH and FADH2
Both NADH and FADH\(_{2}\) carry high-energy electrons to the final stage of cellular respiration, the Electron Transport Chain (ETC). They transfer their captured energy to the protein complexes embedded in the inner mitochondrial membrane. The ETC uses this energy to pump protons (hydrogen ions) from the mitochondrial matrix into the intermembrane space, creating a concentration gradient.
This build-up of protons creates an electrochemical gradient, which is a stored form of energy. The flow of these protons back into the matrix through ATP synthase drives the synthesis of Adenosine Triphosphate (ATP), the cell’s primary energy currency. This process, known as oxidative phosphorylation, is responsible for the vast majority of the ATP generated from glucose.
NADH and FADH\(_{2}\) differ in the amount of ATP they produce because they donate electrons at different points along the Electron Transport Chain. NADH delivers electrons to the first protein complex, powering proton pumping at three distinct points. FADH\(_{2}\), in contrast, enters the chain later at the second protein complex, bypassing the first proton-pumping step. This difference means NADH contributes to a higher ATP yield, generally estimated at about 2.5 ATP per NADH, compared to about 1.5 ATP per FADH\(_{2}\).