CFTR signaling mechanisms and their effects on mitochondria

SANTA COLOMA, TOMAS A; VALDIVIESO, ANGEL G.; CLAUZURE, MARIÁNGELES; MASSIP-COPIZ, MARÍA M; MORI, CONSUELO

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica - SAIC.; 2018

Sociedad Argentina de Investigación Clínica

Mutations in the CFTR gene cause cystic fibrosis. When the CFTR chloride channel was cloned most work fo­ cused on non-genomic effects of CFTR. We instead hypothesized that the complex cystic fibrosis (CF) phe­notype should be the result of the differential regulation of a net of CFTR-dependent genes. By using differential display (DO), we demonstrated that many genes showed differential expression between CF cells and CF "correct­ed" cells. The first CFTR-dependent gene characterized was c-Src, which in turn up-modulated MUC1. Then, we focused in two spots that, contrary to c-Src, showed reduced expression on CF cells. Both DD spots corre­sponded to mitochondrial proteins, MTND4 and CISD1 (a new gene),the first associated to a reduced mitochondrial complex I (mCx-I) activity in CF cells. We then found that IL-1 produced an autocrine positive feed-back loop that increased its own expression and activity and was responsible for the mtCx-1 failure and the increased oxidative stress in CF cells. For the second gene, CISD1, codified by the nuclear genome, it has been very diffi­cult to assign a function, and many distinct functions has been attributed by other authors. Then, we hypothesized that the signal regulating the differential gene expression in CF could be the intracellular Cl- concentration. Thus, by using DD, we found the existence of Cl--dependent genes, including GRLX5 and RPS27, and showed that Cl- was acting as a second-messenger for CFTR. Then, we demonstrated that increased intracellular Cl- induced IL-1 secretion through a complex mechanism not yet com­pletely understood, which might involve several parallel pathways. In fact, we demonstrated that Cl- modulates IL-1 expression and secretion through a novel mecha­nism of NLRP3 inflammasome activation. In conclusion, Cl- behaves as a signaling effector and proinflammatory signal, regulating the expression of specific genes, some of them involved in modulation of mitochondrial activity.