title: Clostridium difficile toxin B causes apoptosis in epithelial cells by thrilling mitochondria. Involvement of ATP-sensitive mitochondrial potassium channels.
abstract: Targeting to mitochondria is emerging as a common strategy that bacteria utilize to interact with these central executioners of apoptosis. Several lines of evidence have in fact indicated mitochondria as specific targets for bacterial protein toxins, regarded as the principal virulence factors of pathogenic bacteria. This work shows, for the first time, the ability of the Clostridium difficile toxin B (TcdB), a glucosyltransferase that inhibits the Rho GTPases, to impact mitochondria. In living cells, TcdB provokes an early hyperpolarization of mitochondria that follows a calcium-associated signaling pathway and precedes the final execution step of apoptosis (i.e. mitochondria depolarization). Importantly, in isolated mitochondria, the toxin can induce a calcium-dependent mitochondrial swelling, accompanied by the release of the proapoptogenic factor cytochrome c. This is consistent with a mitochondrial targeting that does not require the Rho-inhibiting activity of the toxin. Of interest, the mitochondrial ATP-sensitive potassium channels are also involved in the apoptotic response to TcdB and appear to be crucial for the cell death execution phase, as demonstrated by using specific modulators of these channels. To our knowledge, the involvement of these mitochondrial channels in the ability of a bacterial toxin to control cell fate is a hitherto unreported finding.
authors.affiliation: Department of Drug Research and Evaluation, Istituto Superiore di Sanita', Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Loredana
authors.initials: L
authors.lastname: Falzano
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Gambardella
authors.forename: Claudio
authors.initials: C
authors.lastname: Frank
authors.forename: Blandine
authors.initials: B
authors.lastname: Geny
authors.forename: Michel R
authors.initials: MR
authors.lastname: Popoff
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D017209:Apoptosis; D001426:Bacterial Proteins / Q000502:physiology*; D001427:Bacterial Toxins; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C031815:toxB protein, Clostridium difficile; D000255:Adenosine Triphosphate; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D002118:Calcium