Mitochondrial oxidative phosphorylation

Hinkle, P.C., Kumar, M. A., Rasetar, A., Harris, D.L. (1991). Mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Biochemistry 30, 3576-3582. 

The lower trialky Itin compounds are able to inhibit mitochondrial, oxidative phosphorylation (471,477) and, therefore, disrupt the funda-... 

Apart from gastropods, harmful effects of TBT have also been demonstrated in oysters (Environmental Health Criteria 116, Thain and Waldock 1986). Early work established that adult Pacific oysters (Crassostrea gigas) showed shell thickening caused by the development of gel centers when exposed to 0.2 pg/L of TBT fluoride (Alzieu et al. 1982). Subsequent work established the no observable effect level (NOEL) for shell thickening in this, the most sensitive of the tested species, at about 20 ng/L. It has been suggested that shell thickening is a consequence of the effect of TBT on mitochondrial oxidative phosphorylation (Alzieu et al. 1982). Reduced ATP production may retard the function of Ca++ ATPase, which is responsible for the Ca++ transport that leads to CaCOj deposition during the course of shell formation. Abnormal calcification causes distortion of the shell layers. 

Hinkle PC et al Mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Biochemistry 1991 30 3576. 

Disorders of mitochondrial oxidative phosphorylation Proteins encoded by mitochondrial genes Proteins encoded by nuclear genes... 

ATP certainly fulfils the criteria for a NT. It is mostly synthesised by mitochondrial oxidative phosphorylation using glucose taken up by the nerve terminal. Much of that ATP is, of course, required to help maintain Na+/K+ ATPase activity and the resting membrane potential as well as a Ca +ATPase, protein kinases and the vesicular binding and release of various NTs. But that leaves some for release as a NT. This has been shown in many peripheral tissues and organs with sympathetic and parasympathetic innervation as well as in brain slices, synaptosomes and from in vivo studies with microdialysis and the cortical cup. There is also evidence that in sympathetically innervated tissue some extracellular ATP originates from the activated postsynaptic cell. While most of the released ATP comes from vesicles containing other NTs, some... 

Figure 13.2 Schematic representation of a possible ATP, purinergic, synapse. The effects of ATP, synthesised intraneuronally by mitochondrial oxidative phosphorylation from glucose, on various neuronal ATPases, are shown together with its actions as a conventional neurotransmitter acting at postsynaptic P2 and presynaptic Pj receptors...

The mechanism for the production of O2" in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the... 

Leite AZ, Sipahi AM, Damiao AO, Coelho AM, Garcez AT, Machado MC, Buchpiguel CA, Lopasso FP, Lordello ML, Agostinho CL, Laudanna AA Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID A new mechanism. Gut 2001 48 163-167. 

The answer is d. (Hardman, p 1019J Niclosamide is a halogenated salicylanilide derivative. It exerts its effect against cestodes by inhibition of mitochondrial oxidative phosphorylation in the parasites. The mechanism of action is also related to its inhibition of glucose and oxyrgen uptake in the parasite. 

The chemi-osmotic theory of oxidative phosphorylation has been reviewed,74 a model for mitochondrial oxidative phosphorylation in which a membrane potential or proton gradient might transmit energy from an oxidation step to ATP synthesis has been proposed,76 and adenine nucleotide transport in mitochondria has been reviewed.76... 

In contrast to substrate level phosphorylation in glycolysis, mitochondrial oxidative phosphorylation is an efficient process in that it generates in excess of 30 ATP per mole of glucose. In essence, the movement of electrons along the respiratory chain or electron transport chain is coupled with phosphorylation of ADP. 

Muscle contraction produces ADP if this cannot be recycled to ATP contraction will cease. Rephosphorylation of ADP by mitochondrial oxidative phosphorylation is an... 

During periods of recovery following exercise, creatine phosphate is regenerated at the expense of ATP synthesized from mitochondrial oxidative phosphorylation energy currency is paid into a reserve account, or reservoir, for the next period of sustained exercise. 

Murphy MP. Slip and leak in mitochondrial oxidative phosphorylation. Biochim Biophys Acta 1989 977 123-141. 

Peterson et al. found an increase in intramyocellular lipid content and reduction in mitochondria phosphorylation (mitochondrial rates of ATP production) in insulin-resistant subjects versus insulin-sensitive subjects. They concluded that their results supported the h) othesis that insulin resistance is due to dysregulation of intramyocellular fatty acid metabolism, which maybe caused by an inherited defect in mitochondrial oxidative phosphorylation. 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

Certain foreign compounds can cause changes in body temperature, which may become a toxic response if they are extreme. Substances such as 2,4-dinitrophenol and salicylic acid will raise body temperature, as they uncouple mitochondrial oxidative phosphorylation. Thus, the energy normally directed into ATP during oxidative phosphorylation is released as heat. Substances that cause vasodilation may cause a decrease in body temperature. 

How is a concentration gradient of protons transformed into ATP We have seen that electron transfer releases, and the proton-motive force conserves, more than enough free energy (about 200 lcJ) per mole of electron pairs to drive the formation of a mole of ATP, which requires about 50 kJ (see Box 13-1). Mitochondrial oxidative phosphorylation therefore poses no thermodynamic problem. But what is the chemical mechanism that couples proton flux with phosphorylation ... 

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