Neurons derive their energy in the form of ATP from the oxidation of glucose. Initially glucose is oxidized to pyruvate in the PHA-665752 concentration cytosol through glycolysis. The pyruvate is transported into the mitochondrial matrix where it is converted to acetyl co-enzyme A (ACoA) by pyruvate dehydrogenase. AcoA enters the citric acid cycle, in which the acetyl group is oxidized
to carbon dioxide. In the citric acid cycle, NAD+ is reduced to NADH and FAD is reduced to FADH2. NADH and FADH2 are the substrates for oxidative phosphorylation Inhibitors,research,lifescience,medical (Fig. 1). Oxidative phosphorylation is carried out by five multiprotein complexes. Complexes I–IV form an electron transport chain (ETC) where electrons are donated to oxygen at Complex IV. Protons are pumped from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates an electrochemical
Inhibitors,research,lifescience,medical gradient or proton motive force that is used by Complex V to drive the conversion of ADP to ATP. Three protons passing back from the intermembrane space to the matrix are necessary to convert one molecule of ADP to ATP (Mitchell 1961, 1966). Not all electrons entering the ETC are passed to Complex IV. Some electrons escape to oxygen Inhibitors,research,lifescience,medical at Complexes I and III, giving rise to the formation of harmful reactive oxygen species (ROS) (Skulachev 1996, 1997, 1998; Korshunov et al. 1997). Inhibitors,research,lifescience,medical ROS formation is particularly high when Complex I is inhibited (Votyakova and Reynolds 2001). Although cells have evolved ways of dealing with ROS once formed a means of preventing or minimizing ROS formation is energetically advantageous. Thus, a leak of protons back to the matrix, bypassing Complex V, results in a major reduction in ROS formation while having a minimal effect on ATP synthesis. A slight decrease in the potential difference across inner mitochondrial membrane has been shown to inhibit H2O2 formation by 70% (Hansford et al. 1997; Votyakova and Reynolds 2001; Echtay 2007) (Fig. 1). Figure 1 Oxidative phosphorylation in mitochondrial electron
transport chain Inhibitors,research,lifescience,medical (ETC), and proton leak via uncoupling proteins (UCPs). UCP dissipates mitochondrial membrane potential by facilitating proton leak across the inner membrane, thereby minimizing superoxide … Therefore, it is not Calpain surprising that primitive life forms evolved a protein that could bring about such a regulated leak, thereby uncoupling the electron transport and proton export aspects of the oxidative phosphorylation process from ATP synthesis. However, the ability of a protein to undertake uncoupling does not rule out the possibility that other tasks could be performed also, such as regulation of intracellular calcium or synaptic function (Jezek 2002; Andrews et al. 2005). UCPs 4 and 5 Human UCP4 was first identified as a novel member of the human UCP family (Mao et al. 1999). The gene encoding the protein is located on chromosome 6p11.2-q12.