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 (Ub₀), ubiquinone 5 (Ub₅) and ubiquinone 10 (Ub₁₀) on PTP regulation, H₂O₂ production and cell viability in U937 cells. We found that Ub₀ induced both PTP opening and H₂O₂ production. Ub₅ did not regulate PTP opening yet induced H₂O₂ production. Ub₁₀ potently inhibited PTP opening yet induced H₂O₂ production. Both Ub₀ and Ub₅ induced cell death, whereas Ub₁₀ was not toxic. Moreover, Ub₁₀ 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.