The oxidation of acetyl CoA to CO2 is coupled to the reduction of NAD+ and FAD to NADH and FADH2, respectively. Most of the energy derived from oxidative metabolism is then produced by the process of oxidative phosphorylation (discussed in detail in the next section), which takes place in the inner mitochondrial membrane. The high-energy electrons from NADH and FADH2 are transferred through a series of carriers in the membrane to molecular oxygen. The energy derived from these electron transfer reactions is converted to potential energy stored in a proton gradient across the membrane, which is then used to drive ATP synthesis. The inner mitochondrial membrane thus represents the principal site of ATP generation, and this critical role is reflected in its structure. First, its surface area is substantially increased by its folding into cristae. In addition, the inner mitochondrial membrane contains an unusually high percentage (greater than 70%) of proteins, which are involved in oxidative phosphorylation as well as in the transport of metabolites (e.g., pyruvate and fatty acids) between the cytosol and mitochondria. Otherwise, the inner membrane is impermeable to most ions and small molecules—a property critical to maintaining the proton gradient that drives oxidative phosphorylation.