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* Corresponding author 1 LBFA - Bioenergétique fondamentale et appliquée

Abstract : BACKGROUND: 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.
METHODOLOGY-PRINCIPAL FINDINGS: The 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-SIGNIFICANCE: We 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.






Autor: Flavien Devun - Ludivine Walter - Julie Belliere - Cécile Cottet-Rousselle - Xavier Leverve - Eric Fontaine -

Fuente: https://hal.archives-ouvertes.fr/



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