The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis

What is it about?

Cystic fibrosis (CF) is a disease produced by mutations in the CFTR channel. We have previously reported that the CFTR chloride transport activity indirectly regulates the differential expression of several genes, including SRC and MUC1. Here we report that MT-ND4, a mitochondrial gene encoding a subunit of the mitochondrial Complex I (mtCx-I), is also a CFTR-dependent gene. A reduced expression of MT-ND4 was observed in CFDE cells (derived from a CF patient) when compared to CFDE cells ectopically expressing wild-type CFTR. The differential expression of MT-ND4 in CF was confirmed by RT-PCR. In situ hybridizations of deparaffinized human lung tissue slices derived from wt-CFTR or CF patients also showed downregulation of ND4 in CF. In addition, the CFTR chloride transport inhibitors glibenclamide and CFTR(inh)-172 also reduced MT-ND4 expression in CFDE cells ectopically expressing wt CFTR.

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Why is it important?

These results suggest that the CFTR chloride transport activity indirectly up-regulates MT-ND4 expression. Allowed us to find later that the mitochondrial complex I activity was impaired in CF cells. Related work from our lab: 1: Valdivieso ÁG, Dugour AV, Sotomayor V, Clauzure M, Figueroa JM, Santa-Coloma TA. N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells. Redox Biol. 2018 Jun;16:294-302. doi: 10.1016/j.redox.2018.03.006. Epub 2018 Mar 14. PubMed PMID: 29573703. 2: Clauzure M, Valdivieso AG, Massip Copiz MM, Schulman G, Teiber ML, Santa-Coloma TA. Disruption of interleukin-1β autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2014 Jun 5;9(6):e99257. doi: 10.1371/journal.pone.0099257. eCollection 2014. PubMed PMID: 24901709; PubMed Central PMCID: PMC4047112. 3: Valdivieso AG, Santa-Coloma TA. CFTR activity and mitochondrial function. Redox Biol. 2013 Feb 5;1:190-202. doi: 10.1016/j.redox.2012.11.007. Review. PubMed PMID: 24024153; PubMed Central PMCID: PMC3757715. 4: Valdivieso AG, Clauzure M, Marín MC, Taminelli GL, Massip Copiz MM, Sánchez F, Schulman G, Teiber ML, Santa-Coloma TA. The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2012;7(11):e48059. doi: 10.1371/journal.pone.0048059. Epub 2012 Nov 21. PubMed PMID: 23185247; PubMed Central PMCID: PMC3504030. 5: Valdivieso ÁG, Clauzure M, Massip-Copiz M, Santa-Coloma TA. The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes. Cell Physiol Biochem. 2016;38(1):49-64. doi: 10.1159/000438608. Epub 2016 Jan 8. PubMed PMID: 26741366. 6: Clauzure M, Valdivieso ÁG, Massip-Copiz MM, Mori C, Dugour AV, Figueroa JM, Santa-Coloma TA. Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells. J Cell Biochem. 2017 Aug;118(8):2131-2140. doi: 10.1002/jcb.25850. Epub 2017 Apr 18. PubMed PMID: 27996167. 7: Massip-Copiz MM, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. CFTR impairment upregulates c-Src activity through IL-1β autocrine signaling. Arch Biochem Biophys. 2017 Feb 15;616:1-12. doi: 10.1016/j.abb.2017.01.003. Epub 2017 Jan 11. PubMed PMID: 28088327. 8: Massip Copiz MM, Santa Coloma TA. c- Src and its role in cystic fibrosis. Eur J Cell Biol. 2016 Oct;95(10):401-413. doi: 10.1016/j.ejcb.2016.08.001. Epub 2016 Aug 11. Review. PubMed PMID: 27530912. 9: Massip-Copiz M, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. Epiregulin (EREG) is upregulated through an IL-1β autocrine loop in Caco-2 epithelial cells with reduced CFTR function. J Cell Biochem. 2018 Mar;119(3):2911-2922. doi: 10.1002/jcb.26483. Epub 2017 Nov 24. PubMed PMID: 29091309.

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