Uncoupling of Oxidative Phosphorylation

Basic Mechanisms Energy coupling in the respiratory chain results in the generation of ATP from ADP and inorganic phosphate at the expense of energy. This energy is provided by the electron transport chain. The oxidative phosphorylation system is localized in the inner mitochondrial membrane. Uncoupling agents allow electron transport to oxygen to continue but prevent the phosphorylation of ADP to ATP, that is, they uncouple the energy-yielding from the energy-saving process. This results in increased mitochondrial oxygen uptake and reduced ATP levels despite an increased ATP-synthase activity.

The energy-yielding and energy-requiring processes are coupled by a high-energy intermediate state. An electrochemical gradient of H+ ions across the mitochondrial inner membrane serves as means of coupling the energy flow from electron transport to the formation of ATP. An intact mito-chondrial membrane that is impermeable to H + ions is essential for maintaining the proton gradient, necessary for oxidative phosphorylation. The electron transport chain pumps H+ ions outward, and ATP formation is accompanied by an inward H+ movement. Uncoupling agents, such as salicylate, allow protons to cross the otherwise impermeable membrane, thus destroying the proton gradient (Figure 2.22).

The system is devised as not to waste energy when it is not needed. When the utilization of ATP is low, there is little ADP in the mitochondrial matrix, little re-entry of protons through ATP synthase, and the high proton gradient slows down the activity of the respiratory chain by inhibition of ATP release from the ATP synthase. If ATP is consumed, the concentration of ADP increases, protons re-enter the matrix through ATP synthase and regenerate ATP. The electron transport through the respiratory chain causes H+ to be pumped outward across the inner membrane of the mitochondrion, resulting in a gradient of H+. This gradient is the energy-rich state to which electron transport energy is transformed and is the immediate driving force for the phosphorylation of ADP. The maintenance of this gradient, that is, the impermeability of the inner mitochondrial membrane for H +, is essential for the functioning of this coupling process (Figure 2.22).

Figure 2.22 Oxidative phosphorylation in the absence (a) and presence (b) of salicylates. An electrochemical gradient of H + ions across the mitochondrial inner membrane couples the energy flow from electron transport to the generation of ATP. An intact mitochondrial membrane that is impermeable to H+ ions is essential for maintaining the proton gradient. The electron transport chain pumps H+ ions outward ffi whereas ATP formation is accompanied by an inward H + movement ffl. (a) Salicylateworksasa protonophoreand increases the number of proton channels. This results in a more than fourfold increase in membrane conductance at 1 mM due to the weak anion current at neutral pH at which the compound is present as a lipid-soluble anion (the internal hydrogen bond delocalizes the negative charge). As a consequence, the proton gradient and membrane potential decrease and increased oxygen and substrate consumption will be required to maintain the protonmotive force. The increased proton accumulation inside the mitochondrion stimulates H+/Na+ exchange, resulting in mitochondrial swelling © (b).

Oxidative phosphorylation

Oxidative phosphorylation

Intermembrane space

mitochondrial matrix

O Electron transfer chain: Electrons are removed from MADH or FADH; and passed so the terminal electron acceptor 02 via a series of redox reactions thereby forming ot a proton gradient across Ihe mitochondrial inner membrane.

ATP synthase: Since membranes are impermeable for protons the protons that reenter the matrix pass Ihraugh special proton channel proteins called ATP synthase. The energy derived frorr the movement of these protons is used to synthesize ATP from ADP and phosphale

Salicylate increases the number ol proton channels available by competing for the proton [uncoupling) to lorm salicylic acid, leading to a decrease in protonmotive force and depletion of ATP.

Influx of fluid due to accumulation of sodium.

Was this article helpful?

0 0

Post a comment