Mitochondrial effects

Milanesi, E., Costantini, P., Gambalunga, A., Colonna, R., Petronilli, V., Cabrelle, A., Semenzato, G., Cesura, A. M., Pinard, E., and Bernardi, P., 2006, The mitochondrial effects of small organic ligands of BCL-2 Sensitization of BCL-2-overexpressing cells to apoptosis by a pyrimidine-2,4,6-trione derivative, J. Biol. Chem. 281, pp. 10066-10072... 

Kong JY, Rabkin SW. Mitochondrial effects with ceramide-induced cardiac apoptosis are different from those of palmitate. Arch Biochem Biophys 2003 412 196-206. 

The exact mechanism of aminoglycoside nephrotoxicity is unclear. As discussed above, release of lysosomal enzymes can contribute to altered cellular function. Hydroxy radicals may also play a role in aminoglycoside mitochondrial effects, since catalase inhibits in vitro alterations of mitochondrial function by gentamicin and the use of hydroxy radical scavengers or iron chelators reduces gentamicin nephrotoxicity in vivo. Additionally,... 

Mitochondrial effects GSH depletion ATP depletion Phospholipid modifications Heat shock protein modifications Lipid peroxidation Inhibition of membrane potential Ca release into cytosol... 

The following sections provide an in-depth analysis of the proposed MOA for rat and mouse liver tumors induced by PPARa activators. This analysis is not intended to reflect an exhaustive review of the literature but rather a sununation of key evidence. This review of the data did not consider alternative effects of PPARa activators, including mitochondrial effects, gap junction intercellular communication (GJIC), or methylation of DNA, because the data are weak or a direct causal link to liver tumor induction is lacking. 

Fall et al. investigated the role of the mitochondrial transition pore (MTP) in apoptosis induced by the Parkinsonism producing toxin N-methyl pyridinium ion (MPP+) by using cyclosporin A (CSA) alone or in combination with the phospholipase A2 (PLA2) inhibitor aristolochic acid (5) (ARA). In this experiment, aristolochic acid alone inhibited MPP+ induced apoptosis at 24 hours but did not alter the mitochondrial effects of MPP+, suggesting that ARA inhibits MPP+ induced apoptosis downstream of the initiation event. Thus, ARA may prove to be another useful tool for understanding apoptosis [455,456]. 

MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16(l) 29-37 Varbiro G, Toth A, Tapodi A, Veres B, Sumegi B, Galiyas F Jr (2003) Concentration dependent mitochondrial effect of amiodarone. Biochem Pharmacol 65(7) 1115-1128 Velsor LW, Kovacevic M, Goldstein M, Leitner HM, Lewis W, Day BJ (2004) Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. Toxicol Appl Pharmacol 199 (1) 10-19... 

Fig. 17 Mitochondrial effects of valproic acid. Valproic acid freely enters mitochondria, and thus translocates protons into the mitochondrial matrix. This protonophoric effect can slightly imcouple mitochondrial respiration, and can help trigger mitochondrial permeability transition (MPT). Inside the matrix, valproate is extensively transformed into valproyl-CoA, thus sequestering intramitochondrial CoA. The lack of CoA impairs both mitochondrial fatty acid 6-oxidation and pyruvate oxidation. Valproate is also dehydrogenated by cytochrome P450 (CYP) into 4-ene-valproate, which then forms 4-ene-valproyl-CoA and 2,4-diene-valproyl-CoA within mitochondria. The latter is an electrophilic metabolite, which may inactivate 6-oxidation enzymes...

Mitochondrial cytopathies affect mitochondrial respiration, which may secondarily inhibit p-oxidation, as explained above. Mitochondrial cytopathies may therefore be revealed during the administration of drugs that have mitochondrial effects. Thus, the administration of valproate, which inhibits mitochondrial p-oxidation and pyruvate-supported respiration, may reveal a previously latent mitochondrial cytopathy (Chabrol et al. 1994 Lam et al. 1997 Krahenbiihl et al. 2000). For the same reasons, valproate administration can also reveal an inborn p-oxidation defect (Nj0lstad et al. 1997 Kottlors et al. 2001). 

Murakami K, Nishiyama K, Higuti T. 1986b. Mitochondrial effect of orally administered dibutyl phthalate in rats. Nippon Eiseigaku Zasshi (Jpn J Hyg) 41(4) 769-774. 

T. Serafim, J. Matos, V. Sardao, G. Pereira, A. Branco, S. Pereira, D. Parke, E. Perkins, A. Moreno, J. Holy, and P. Oliveira, Sanguinarine cytotoxicity on mouse melanoma K1735-M2 cells—nuclear vs. mitochondrial effects. Biochem. Pharmacol, 76 (2008) 1459-75. 

It is interesting to note that on the National Cancer Institute s files there are 70 compounds which contain the substructure P -C and also have shown activity against the primary screen P388 leukaemia. It might be expected that if mitochondrial effects were important then the degree of cytotoxicity would be related to the degree of lipophilicity of the phosphonium salts. Thus aryl-substituents may produce a greater cytotoxic effect than alkyl-substituents. 

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