Down-regulation of the mitochondrial gene ND4 in Cystic Fibrosis.

VALDIVIESO, A. G.; TAMINELLI, G.L.; TEIBER, M.L; DANKERT, M.A.; SANTA COLOMA, T.A.

Rosario, Santa Fé, Argentina

Congreso; XLII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2006

SAIB

Cystic Fibrosis (CF) is a frequent genetic disease produced by mutations in the CFTR chloride channel. We have previously identified the subunit ND4 of the mitochondrial Complex I (mCx I) as a CFTR-dependent gene. Our objective is now to confirm its CFTR-dependency and to determine whether the failure in the Cl- transport by CFTR induces a reduced mCx-I activity. Blue Native-PAGE were used to measure the mCx-I activity on mitochondria extracted from cells derived from a patient with CF (CFDE cells), the same cells ectopically expressing wt CFTR, and T84 cells (expressing wt CFTR). A significant decrease of the activity of the mCx-I was observed between CFDE and CFDE/6RepCFTR, an effect that could also be obtained on T84 cells by using glibenclamide. We are now confirming these results with the new CFTR inhibitor (CFTR(inh)-172), which is more specific and potent than glibenclamide. The differential expression of ND4 could also be reverted by using the CFTR inhibitor glibenclamide or CFTR(inh)-172, confirming that ND4 expression can be modulated by the CFTR chloride transport activity. These results might explain the mitochondrial abnormalities reported by other authors in CF, for which the mechanisms are not known yet. Acknowledgments: University of Buenos Aires, CONICET, ANPCYT and Ministry of Health (Carrillo Oñativia Fellowship).