All-trans-retinoic acids (ATRA) is one of the biologically active metabolites of vitamin A which plays an important role in cell differentiation and proliferation (MB. Reeves et al. 2007, Science). The molecular basis of its action has not been fully elucidated. It was previously shown (F. Papa et al. 2007, Int.J.Immun.Pharm.) that ATRA treatment of normal human keratinocytes resulted in growth suppression, increase of complex I content and reduction of the NADH-UQ oxidoreductase enzymatic activity. These effects were associated with enhanced level of GRIM-19. We found that induction of cAMP-PKA signalling, by dibutyryl cyclic AMP or okadaic acid, restores the complex I activity inhibited by ATRA, indicating an interplay between ATRA and PKA signal transduction on regulation of cellular bioenergetics. Mitochondrial proteome has to be considered as a non-static entity, that shows characteristic changes according to the functional state of the cell. To monitor the effect of ATRA on mitochondria keratinocytes protein profile a widesearch proteomic approach was used. In ATRA treated cells, a large number of mitochondrial proteins, were found to be up or down expressed with respect to control cells. In particular ATRA cell-treatment appeared to affect proteins which are synthesized in very low amount, as the case of regulatory proteins. Two proteins spots, down regulated in mitochondria of ATRA treated keratinocytes, were identified by mass spectrometry analysis as ATP synthase beta subunit, component of complex V, and protein disulfide-isomerase A6. These results indicate an effect of ATRA on the expression of mitochondrial OXPHOS complexes.
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