title: Transglutaminase overexpression sensitizes neuronal cell lines to apoptosis by increasing mitochondrial membrane potential and cellular oxidative stress.
abstract: 'Tissue' transglutaminase (tTG) selectively accumulates in cells undergoing apoptosis both in vivo and in vitro. Considering the central role played by mitochondria in apoptosis, we investigated the relationships existing amongst tTG expression, apoptosis and mitochondrial function. To this aim we studied the mechanisms of apoptosis in a neuronal cell line (SK-N-BE (2)) in which the tTG-expression was driven by a constitutive promoter. Furthermore, a tet-off inducible promoter was also used in 3T3 fibroblastic cells used as control. Both cell lines, when expressing tTG, appeared 'sensitized' to apoptosis. Strikingly, we found major differences in the morphological features of mitochondria among cell lines in the absence of apoptotic stimuli. In addition, these ultrastructural characteristics were associated with specific functional features: (i) constitutively hyperpolarized mitochondria and (ii) increased reactive oxygen intermediates production. Importantly, after mitochondrial-mediated apoptosis by staurosporine, a rapid loss of mitochondrial membrane potential was found in tTG cells only. Taken together, these results seem to suggest that, via hyperpolarization, tTG might act as a 'sensitizer' towards apoptotic stimuli specifically targeted to mitochondria. These results could also be of pathogenetic relevance for those diseases that are characterized by increased tTG and apoptotic rate together with impaired mitochondrial function, e.g. in some neurodegenerative disease.
authors.affiliation: Department of Biology, University of Rome Tor Vergata Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Farrace
authors.forename: Lucia
authors.initials: L
authors.lastname: Piredda
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Fabiola
authors.initials: F
authors.lastname: Ciccosanti
authors.forename: Laura
authors.initials: L
authors.lastname: Falasca
authors.forename: Carlo
authors.initials: C
authors.lastname: Rodolfo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Giammarioli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Verderio
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002648:Child; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D013752:Tetracycline