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.