title: Elevated CO(2) levels cause mitochondrial dysfunction and impair cell proliferation.
abstract: Elevated CO(2) concentrations (hypercapnia) occur in patients with severe lung diseases. Here, we provide evidence that high CO(2) levels decrease O(2) consumption and ATP production and impair cell proliferation independently of acidosis and hypoxia in fibroblasts (N12) and alveolar epithelial cells (A549). Cells exposed to elevated CO(2) died in galactose medium as well as when glucose-6-phosphate isomerase was knocked down, suggesting mitochondrial dysfunction. High CO(2) levels led to increased levels of microRNA-183 (miR-183), which in turn decreased expression of IDH2 (isocitrate dehydrogenase 2). The high CO(2)-induced decrease in cell proliferation was rescued by α-ketoglutarate and overexpression of IDH2, whereas proliferation decreased in normocapnic cells transfected with siRNA for IDH2. Also, overexpression of miR-183 decreased IDH2 (mRNA and protein) as well as cell proliferation under normocapnic conditions, whereas inhibition of miR-183 rescued the normal proliferation phenotype in cells exposed to elevated levels of CO(2). Accordingly, we provide evidence that high CO(2) induces miR-183, which down-regulates IDH2, thus impairing mitochondrial function and cell proliferation. These results are of relevance to patients with hypercapnia such as those with chronic obstructive pulmonary disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, and muscular dystrophies.
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors: Christine U
authors: CU
authors: Vohwinkel
authors: Emilia
authors: E
authors: Lecuona
authors: Haying
authors: H
authors: Sun
authors: Natascha
authors: N
authors: Sommer
authors: István
authors: I
authors: Vadász
authors: Navdeep S
authors: NS
authors: Chandel
authors: Jacob I
authors: JI
authors: Sznajder
mesh_terms: D002245:Carbon Dioxide / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D006935:Hypercapnia / Q000378:metabolism* / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008171:Lung Diseases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D007656:Ketoglutaric Acids; C533449:MIRN183 microRNA, human; D035683:MicroRNAs; D002245:Carbon Dioxide; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase