Uncoupling proteins (UCP) are found in the inner mitochondrial membrane of mammals, including humans. These proteins create channels that enable H+ to reenter the mitochondrial matrix without capturing energy as ATP. Instead, the energy is released as heat, a process known as nonshivering thermogenesis. UCP1, also called thermogenin, is responsible for heat production in the mitochondria-rich brown adipocytes of mammals. Cold temperatures trigger the catecholamine-dependent activation of UCP1 expression. In response to cold, brown fat, which is present in infants and has been recently discovered in adults, utilizes approximately 90% of its respiratory energy for thermogenesis, while white fat primarily stores energy.

There are also synthetic uncouplers that can disrupt electron transport and the phosphorylation of ADP by shuttling H+ across the inner mitochondrial membrane, dissipating the gradient. A well-known example of a synthetic uncoupler is 2,4-dinitrophenol, which is a lipophilic H+ carrier that readily diffuses through the mitochondrial membrane. Similar to UCP, this uncoupler accelerates electron transport without establishing a H+ gradient, resulting in the release of energy as heat instead of ATP synthesis. Additionally, high doses of aspirin and other salicylates can uncouple oxidative phosphorylation, causing fever in cases of toxic overdoses.

The inner mitochondrial membrane is generally impermeable to charged or hydrophilic substances. However, it contains various transport proteins that facilitate the passage of specific molecules from the cytosol to the mitochondrial matrix.

ATP and ADP transport within the inner membrane relies on specialized carriers. An adenine nucleotide antiporter imports one ADP from the cytosol into the matrix while exporting one ATP from the matrix into the cytosol. Furthermore, a symporter transports Pi and H+ from the cytosol into the matrix.

The inner mitochondrial membrane lacks an NADH transporter, making it impossible for NADH produced in the cytosol to enter the mitochondrial matrix directly. However, reducing equivalents of NADH can be transported from the cytosol into the matrix through substrate shuttles. The glycerol 3-phosphate shuttle involves the transfer of two electrons from NADH to dihydroxyacetone phosphate by cytosolic glycerol 3-phosphate dehydrogenase. The resulting glycerol 3-phosphate is oxidized by the mitochondrial isozyme as FAD is reduced to FADH2. CoQ of the electron transport chain oxidizes the FADH2, ultimately yielding two ATP for each cytosolic NADH oxidized. On the other hand, the malate-aspartate shuttle generates NADH in the mitochondrial matrix, producing three ATP for each cytosolic NADH oxidized by malate dehydrogenase as oxaloacetate is reduced to malate. A transport protein is responsible for moving malate into the mitochondrial matrix.
Uncoupling proteins: Uncoupling proteins (UCP) occur in the inner mitochondrial membrane of mammals, including humans. These proteins form channels that allow H+ to reenter the mitochondrial matrix without energy being captured as ATP (Fig. 6.15). The energy is released as heat, and the process is called nonshivering thermogenesis. UCP1, also called thermogenin, is responsible for heat production in the mitochondria-rich brown adipocytes of mammals. [Note: Cold causes catecholamine-dependent activation of UCP1 expression.] In brown fat, unlike the more abundant white fat, ~90% of its respiratory energy is used for thermogenesis in infants in response to cold. Thus, brown fat is involved in energy expenditure, whereas white fat is involved in energy storage. [Note: Brown fat depots have recently been shown to be present in adults.] d.
Synthetic uncouplers: Electron transport and phosphorylation of ADP can also be uncoupled by compounds that shuttle H+ across the inner mitochondrial membrane, dissipating the gradient. The classic example is 2,4-dinitrophenol, a lipophilic H+ carrier (ionophore) that readily diffuses through the mitochondrial membrane (Fig. 6.16). This uncoupler causes electron transport to proceed at a rapid rate without establishing a H+ gradient, much as do the UCP. Again, energy is released as heat rather than being used to synthesize ATP. [Note: In high doses, aspirin and other salicylates uncouple oxidative phosphorylation. This explains the fever that accompanies toxic overdoses of these drugs.]
B. Membrane transport systems
The inner mitochondrial membrane is impermeable to most charged or hydrophilic substances. However, it contains numerous transport proteins that permit passage of certain molecules from the cytosol to the mitochondrial matrix.
1.
ATP and ADP transport: The inner membrane requires specialized carriers to transport ADP and Pi from the cytosol (where ATP is hydrolyzed to ADP in many energy-requiring reactions) into mitochondria, where ATP can be resynthesized. An adenine nucleotide antiporter imports one ADP from the cytosol into the matrix, while exporting one ATP from the matrix into the cytosol (see Fig. 6.13). A symporter cotransports Pi and H+ from the cytosol into the matrix.
2.
Reducing equivalent transport: The inner mitochondrial membrane lacks an NADH transporter, and NADH produced in the cytosol (for example, in glycolysis; see p. 101) cannot directly enter the mitochondrial matrix. However, reducing equivalents of NADH are transported from the cytosol into the matrix using substrate shuttles. In the glycerol 3phosphate shuttle (Fig. 6.17A), two electrons are transferred from NADH to dihydroxyacetone phosphate by cytosolic glycerol 3-phosphate dehydrogenase. The glycerol 3-phosphate produced is oxidized by the mitochondrial isozyme as FAD is reduced to FADH2. CoQ of the ETC oxidizes the FADH2. Therefore, the glycerol 3-phosphate shuttle results in the synthesis of two ATP for each cytosolic NADH oxidized. This contrasts with the malate-aspartate shuttle (Fig. 6.17B), which produces NADH (rather than FADH2) in the mitochondrial matrix, thereby yielding three ATP for each cytosolic NADH oxidized by malate dehydrogenase as oxaloacetate is reduced to malate. A transport protein moves malate into the mitochondrial matrix.