Oxidized mitochondrial hpids

Nitric oxide-induced apoptosis in human leukemic lines requires mitochondrial hpid degradation and cytochrome c release. Blood 93 2342-2352. 

Chemicals that damage mitochondrial structure, enzymes, or DNA synthesis can disrupt beta oxidation of hpids and oxidative energy production within hepatocytes. Prolonged interruption of beta oxidation leads to micro-vesicular steatosis which can progress to macrovesicular steatosis. This sequence of events has been noted with alcoholic and nonalcoholic steatohepatitis. The role of mitochondria has been extensively studied with nonalcoholic fatty hver disease, a major issue in human medicine. Alcoholic steatosis and other forms of hepatic steatosis have been linked to impairment of ATP homeostasis and mitochondrial abnormalities have been reported in a growing body of hterature. 

Copper is stored by the liver in the storage protein metallothionein and excreted by the transport protein ceruloplasmin into the bile. When 10 rat hepatocytes were incubated with 50 piM Cu " for 2 h, the formation of reactive oxygen species as determined by oxidation of dichlorofluorescin diacetate to dichlorofluorescein increased from 90 5 intensity units in the controls to 412 9 intensity units in the metal-treated cells (Pourahmad and O Brien 2000). Malondialdehyde UV absorption increased from 0.048 0.006 to 0.662 0.012 units obtained at X ax = 532 nm (P <0.001). The ED50 concentrations found for Cu and Cd (i.e. 50% membrane lysis in 2 h) were 50 and 20 pM, respectively (Pourahmad and O Brien 2000). However, reactive oxygen species formation, GSH oxidation and hpid peroxidation were induced by Cu at these concentrations more rapidly than by Cd. The dechne of mitochondrial membrane potential though occurred at the same time and to the same extent for both metals. 

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

In an earlier study of the effects of imipenem in the rabbit kidney it was shown that imipenem caused a significant decrease of mitochondrial respiration, depletion of reduced glutathione, increased production of oxidized glutathione and hpid peroxidation [56]. However, these effects were less than those produced by a comparable nephrotoxic dose of cephaloridine... 

VPA. Histologically, microvesicular steatosis induced by 4-en-VPA is accompanied by ultrastructural changes characterized by myeloid bodies, hpid vacuoles and mitochondrial abnormalities. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial P-oxidation as an important pathogenesis. If the normal pathway of fatty acid oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, decreased CoA would limit the activities of one or more enzymes in the pathway of fatty acid oxidation. 

It is largely accepted that a high dietary intake of poly-unsaturated fatty acids (PUFA) in the co-3 series has beneficial effects. Recently, cellular Hpid metabolism has been suggested as a target for cancer therapy. Cancer cells, compared with normal cells, seem to be vulnerable to exposure of certain polyunsaturated fatty adds (PUFAs), especially those in the to-3 series. Characteristic for these compounds are their poor ability to be oxidized in the cell due to multiple double bonds. They are however likely to be ester-ified to other lipids, and their incorporation into membrane phospholipids will influence membrane properties such as fluidity, protein interactions and susceptibility to lipid peroxidation. The hypolipidemic properties of some (o-3 fatty acids, such as EPA, are probably explained by an induction of mitochondrial 3 -oxidation that is not found after administration of the non-hypolipidemic (o-3 PUFA docosahexaenoic acid (DHA). However, both eicosapentaenoic acid (EPA) and DHA cause increased peroxisomal... 

TTA induces peroxisomal and mitochondrial p-oxidation enzymes in addition to several other enzymes in lipid metabolism. Furthermore, TTA functions as a ligand for PPAR-a and PPAR-y and it stimulates both peroxisomal and mitochondrial proliferation. An increasing amount of genes that are known to carry PPAR response elements (PPREs) is reported, and differential regulation hy these receptors is likely to affect the growth potential. The result of TTA treatment is a reorganization of the cellular hpid metabolism towards an increased metabolic activity. 

Data in the literature clearly show that CLA seems to positively interfere with hpid metabolism, in particular with n-6 PUFAs for eicosanoid formation, mitochondrial and peroxisomal beta oxidation, energy expenditure and eicosanoid catabolism, and with cholesterol metabolism. Most of these data are confined to experimental models, but human studies, even if scarce (especially long-term trials), suggest that CLA enriched products may have a positive impact on human health, extending the dietary inclusion of dairy products to those patients affected by metabolic syndrome. 

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