title: Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death.
abstract: The permeability transition pore (PTP) is a mitochondrial inner membrane channel involved in cell death. The inhibition of PTP opening has been proved to be an effective strategy to prevent cell death induced by oxidative stress. Several ubiquinone analogs are known to powerfully inhibit PTP opening with an effect depending on the studied cell line. Here, we have studied the effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)) and ubiquinone 10 (Ub(10)) on PTP regulation, H(2)O(2) production and cell viability in U937 cells. We found that Ub(0) induced both PTP opening and H(2)O(2) production. Ub(5) did not regulate PTP opening yet induced H(2)O(2) production. Ub(10) potently inhibited PTP opening yet induced H(2)O(2) production. Both Ub(0) and Ub(5) induced cell death, whereas Ub(10) was not toxic. Moreover, Ub(10) prevented tert-butyl hydroperoxide-induced PTP opening and subsequent cell death. We conclude that PTP-inhibitor ubiquinone analogs are able to prevent PTP opening-induced cell death only if they are not toxic per se, which is the case when they have no or low pro-oxidant activity.
authors.affiliation: Inserm, U1055, Grenoble 38041, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Belliere
authors.forename: Flavien
authors.initials: F
authors.lastname: Devun
authors.forename: Cécile
authors.initials: C
authors.lastname: Cottet-Rousselle
authors.forename: Cécile
authors.initials: C
authors.lastname: Batandier
authors.forename: Xavier
authors.initials: X
authors.lastname: Leverve
authors.forename: Eric
authors.initials: E
authors.lastname: Fontaine
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D005452:Fluoresceins; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology*
chemical_list: D016227:Benzoquinones; D005452:Fluoresceins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C109863:ubiquinone-O; D006861:Hydrogen Peroxide; C025204:Ubiquinone Q2; C025203:Ubiquinone Q1; D002118:Calcium; C007740:fluorexon