Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death

Flavien Devun,Cécile Cottet-Rousselle,Eric Fontaine,Xavier Leverve,Julie Belliere,Ludivine Walter,Alfred Lewin

doi:10.1371/journal.pone.0011792

Flavien Devun, Cécile Cottet-Rousselle + Show 5 more

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https://doi.org/10.1371/journal.pone.0011792

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Abstract

BackgroundProlonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet.Methodology/Principal FindingsThe effects of ubiquinone 0 (Ub0), ubiquinone 5 (Ub5), ubiquinone 10 (Ub10) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub0 inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub5 did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub10 regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub5 induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub0 induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism.Conclusions/SignificanceWe found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening.

Highlights

Mitochondria are involved in several physiological processes including energy metabolism, calcium homeostasis and programmed cell death [1,2,3]
Because permeability transition pore (PTP) regulation may be very sensitive to the conditions of incubation used [27,30], we first checked whether PTP regulation by ubiquinone analogs in permeabilized rat hepatocytes was identical to that previously measured in isolated rat liver mitochondria
In this work we have shown that several ubiquinone analogs are able to regulate PTP opening according to the cell type

Summary

Introduction

Mitochondria are involved in several physiological processes including energy metabolism, calcium homeostasis and programmed cell death [1,2,3]. Numerous mitochondrial proteins, which have no pro-apoptotic activity when they remain inside mitochondria, promote cell death once released into the cytosol [4]. Both extra-mitochondrial and intra-mitochondrial signaling pathways can trigger the release of the mitochondrial proapoptotic proteins [2]. A prolonged mitochondrial permeability transition results in a drastic ATP synthesis inhibition through the collapse of the proton-motive force, a dramatic increase in ROS production and the release of the mitochondrial pro-apoptotic proteins [7,8,9]. Permeability transition is due to the opening of an inner membrane channel [10]: the Permeability Transition Pore (PTP). Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet

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