title: The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response.
abstract: Recent findings indicate that prevalent human carcinomas overexpress the mitochondrial ATPase Inhibitory Factor 1 (IF1). Overexpression of IF1 inhibits the synthase activity of the mitochondrial H(+)-ATP synthase and plays a crucial role in metabolic adaptation of cancer cells to enhanced aerobic glycolysis. Herein, we demonstrate that IF1 overexpression in colon cancer cells triggers mitochondrial hyperpolarization and the subsequent production of superoxide radical, a reactive oxygen species (ROS). ROS are required to promote the transcriptional activation of the NFκB pathway via phosphorylation-dependent IκBα degradation. Activation of NFκB results in a cellular adaptive response that includes proliferation and Bcl-xL mediated resistance to drug-induced cell death. Quenching the mitochondrial production of ROS prevents the activation of NFκB and abolishes the IF1-mediated cellular adaptive response. Overall, our findings provide evidence linking the activity of a mitochondrial protein with retrograde signaling to the nucleus to promote cellular proliferation and survival.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Formentini
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Aragó
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Cenizo
authors.forename: José M
authors.initials: JM
authors.lastname: Cuezva
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
chemical_list: D005472:Fluorouracil; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D011506:Proteins; D017382:Reactive Oxygen Species; D019311:Staurosporine; D051020:bcl-X Protein; D000097795:ATPase Inhibitory Protein; C494811:BCL2L1 protein, human; C000606204:NFKBIA protein, human