Interference with mitochondrial function

Therefore, the metabolite interferes with mitochondrial function and decreases the production of ATP and other important cofactors such as NADH and FADH. Therefore, after repeated use of the drug, mitochondrial integrity is reduced and cellular and overall liver fat oxidation is inhibited. Consequently, fat accumulates, seen as microvesicular steatosis. Electron microscopy shows swollen mitochondria and damaged mitochondrial structures. The accumulated lipid may encourage lipid peroxidation and oxidative stress to occur, causing further damage. 

Organotin compounds are readily absorbed through the skin, and skin rashes may result. Organotin compounds, especially those of the R3SnX type, bind to proteins, probably through the sulfur on cysteine and histidine residues. Interference with mitochondrial function by several mechanisms appears to be the mode of biochemical action leading to toxic responses. 

Marked interference with mitochondrial function is a feature of HD brain (Browne and Beal, 2004 Browne et al., 1997 Browne, 2008 Nicholls, 2009 Reddy et al., 2009 Quintanilla and Johnson, 2009 Su et al., 2010). For example, Browne et al. (1997) showed that citrate synthase-corrected complex II-III activity is markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV specific activity is reduced in HD putamen (-62%). Tabrizi et al. (1999) reported that aconi-tase specific activity is reduced to 8,27, and 52% of control activities in HD caudate, putamen, and cerebral cortex, respectively. Tabrizi et al. (2000) also reported that aconitase and complex IV activities are decreased in the striatum of 12-wk HD transgenic (R6/2) mice, and complex IV activity is decreased in cerebral cortex. As noted previously for human HD, oxidative stress indicators (increased inducible NO... 

Eder, S., Benesic, A., Freudinger, R., Engert, J., Schwerdt, G., Drumm, K. and Gekle, M. (2000) Nephritogenic ochratoxin A interferes with mitochondrial function and pH homeostasis in immortalized human kidney ephitelial cells, Pflug. Arch. Eur. J. Phy., 440(4), 521-529. 

Fig. 7. Branch point between fermentation and respiration. At low pyruvate flux, the low of the Pdh complex for pyruvate results in oxidative decarboxylation to form acetyl CoA and NADH. The acetyl CoA can then can go into energy generation (via respiration) or fatty acid synthesis. At high glycolytic flux, pyruvate accumulates, and the higher of Pdc favors acetaldehyde formation and ethanol production. Accumulation of acetate can interfere with mitochondrial function. Pyk Pyruvate kinase Pdh pyruvate dehydrogenase Pdc pyruvate decarboxylase Aid (Dha) aldehyde dehydrogenase Adh alcohol dehydrogenase Acs acetyl CoA synthetase. (Taken from Postma et al. [169])...

The activity of mitochondrial thymidine kinase is sufficiently broad that it will also act on the anti-HIV drug, 3 -azido-2 3 -dideoxythymidine (AZT). That is, the enzyme can phosphorylate AZT to a deoxyribonucleotide of azidothymidine, which is then incorporated into DNA. Evidence suggests that deoxyribonucleotides of AZT interfere with mitochondrial function, possibly by inhibiting mitochondrial DNA replication or transcription, which may explain some of the side effects of cardiotoxicity (damage to the heart muscle) observed with its use. 

Reports of MPP+ interference with mitochondrial function and ATP formation provide an alternative possible mechanism to explain toxicity of MPP+ (for a review, see Gerlach et al., 1991b). 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

Atherosclerosis is not itself a disease but it can lead to a poor supply of blood to tissues/organs, which consequently impairs mitochondrial ATP generation and hence can interfere with the function of that tissue. This leads initially to iU health, but can become sufficiently severe to lead to disease and, eventually, to death (see Chapter 22). 

Numerous toxins are known to interfere with mitochondrial respiratory chain function. These have been used in the development of pesticides and herbicides, and accidental use in man has... 

Atovaguone, USP.. 3- 4-(4-Chlorophenyl)-cyclohexyl -2-hydroxy-1.4-naphthoquinone (Mepron) is a highly lipophilic, water-insoluble analogue of ubiquinone 6. an es.sen-tial componcni of the mitochondrial electron transport chain in micmorganism.s. The. structural similarity between atovaquone and ubiquinone suggests that the former may act as an antimctabolilc for the latter and thereby interfere with the function of electron transport en/ymes. 

The cellular mechanism of direct cephalosporin-induced nephrotoxicity may include several possible actions of the cephalosporins. Nephrotoxic cephalosporins are known to induce lipid peroxidation and cellular membrane damage, acylate cellular proteins, and/or interfere with mitochondrial respiration. Mitochondrial respiration appears to be inhibited due to acylation of mitochondrial transporters for metabolic substrates, thereby depriving mitochondria of the necessary intermediates to utilize oxygen. Ultimately, the formation of adenosine triphosphate (ATP), needed to supply cellular energy, also declines to inhibit energy-dependent cellular functions. 

Whereas inhibition of chloroplast electron transport has been correlated with binding to a protein(s), the sites and mechanisms through which herbicides interfere with mitochondrial and chloroplast mediated phosphorylations remain to be identified. When lipophilic herbicides partition into the lipid phases of membranes, they could perturb lipid-lipid, lipid-protein, and protein-protein interactions that are required for membrane functions such as electron transport, ATP formation, and active transport. Evidence for general membrane perturbations caused by chlorpropham, 2,6-dinitroanilines, perfluidone, and certain phenylureas have been reported previously (8-11). 

Lead is a toxic metal to which there is wide exposure. Exposure is via inhalation (main source, leaded petrol) and ingestion (water, old paint). Multi-organ toxicity occurs with the kidneys, central and peripheral nervous system, testes, red cells, bones, and gastrointestinal tract all damaged. After initial distribution into red blood cells, it is eventually deposited in bone. The main biochemical effect is interference with heme synthesis at several points. Kidney toxicity may be due to lead-protein complexes and inhibition of mitochondrial function. Damage to nerves leads to peripheral neuropathy. 

Figure 8-4. The effect of the MELAS mutation on mitochondrial function is to interfere with function of respiratory Complex I or I and IV, leading to increased levels of NADH and thus also of lactate. CoQ, coenzyme Q MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes RC, respiratory complex.

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