(48) STUDY OF THE ACYL CoA ESTERS AS POTENT INHIBITORS OF THE PERMEABILITY TRANSITION INDUCED BY TNF
Christiane Levrat, Pascal George, Domonique Ardail and Pierre Louisot Recently it was reported that in mitochondria the hexokinase complex exhibited permeability and conductance properties that resembled those of the mitochondrial permeability transition pore. The coupling between the kinases and the adenylate translocase has two functions -- molecular channeling of ATP and ADP, and regulation of the permeability transition. Based on these results we have studied the activities of these enzymes in WEHI-164 and C6 cell lines after TNF treatment . The WEHI-164 cell line is highly sensitive while the C6 cell lines is strongly TNF resistant. In the past we have shown that RNF induced an early permeability transition in the mitochondria of the WEHI-164 cells after 4h treatment. Our work reports that TNF stimulates the activity of hexokinase by 30% in the WEHI-164 cell line only. The adenylate translocase activity is unchanged in C6 cells but it is significantly increased in WEHI-164 cells after 4h TNF treatment. Acyl CoA esters have been shown to be potent inhibitors of adehylate translocase both in intact mitochondria and submitochondrial particles in a specific and chain-length-dependent manner. Under our conditions the basic level of the acyl CoA esters are higher in C6 cells and their compartments mitochondria and cytoplasm than in WEHI-164 cells. TNF treatment induces few changes, only a slight increase of the acyl CoA esters in the C6 cell line especially in mitochondria. The characterization of the acyl moiety is under way. These preliminary results suggest that the level and the nature of the acyl CoA esters could prevcent the permeability transition in mitochondria by keeping closed the permeability transition pore and consequently be one of the factors involved in the mechanism of the cellular RNF resistance.
For further information contact...Carmen Mannella: carmen@wadsworth.org
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