According to the chemiosmotic coupling hypothesis, proposed by Nobel Prize in Chemistry winner Peter D. Mitchell, the electron transport chain and oxidative phosphorylation are coupled by a proton gradient across the inner mitochondrial membrane. The efflux of protons from the mitochondrial matrix creates an electrochemical gradient (proton gradient). This gradient is used by the FF ATP synthase complex to make ATP via oxidative phosphorylation. ATP synthase is sometimes described as Complex V of the electron transport chain. The F component of ATP synthase acts as an ion channel that provides for a proton flux back into the mitochondrial matrix. It is composed of a, b and c subunits. Protons in the inter-membrane space of mitochondria first enter the ATP synthase complex through an a subunit channel. Then protons move to the c subunits. The number of c subunits determines how many protons are required to make the F turn one full revolution. For example, in humans, there are 8 c subunits, thus 8 protons are required. After c subunits, protons finally enter the matrix through an a subunit channel that opens into the mitochondrial matrix. This reflux releases free energy produced during the generation of the oxidized forms of the electron carriers (NAD and Q) with energy provided by O. The free energy is used to drive ATP synthesis, catalyzed by the F component of the complex.<br>Coupling with oxidative phosphorylation is a key step for ATP production. However, in specific cases, uncoupling the two processes may be biologically useful. The uncoupling protein, thermogenin—present in the inner mitochondrial membrane of brown adipose tissue—provides for an alternative flow of protons back to the inner mitochondrial matrix. Thyroxine is also a natural uncoupler. This alternative flow results in thermogenesis rather than ATP production.