Abstract
The permeability transition pore (PTP) is a mitochondrial inner membrane Ca(2+)-sensitive channel that plays a key role in different models of cell death. Because functional links between the PTP and the respiratory chain complex I have been reported, we have investigated the effects of rotenone on PTP regulation in U937 and KB cells. We show that rotenone was more potent than cyclosporin A at inhibiting Ca(2+)-induced PTP opening in digitonin-permeabilized cells energized with succinate. Consistent with PTP regulation by electron flux through complex I, the effect of rotenone persisted after oxidation of pyridine nucleotides by duroquinone. tert-butyl hydroperoxide induced PTP opening in intact cells (as shown by mitochondrial permeabilization to calcein and cobalt), as well as cytochrome c release and cell death. All these events were prevented by rotenone or cyclosporin A. These data demonstrate that respiratory chain complex I plays a key role in PTP regulation in vivo and confirm the importance of PTP opening in the commitment to cell death.
Highlights
Studies over the past few years have led to the recognition that, in addition to their established role in energy metabolism, mitochondria are main actors of cell death
We show that rotenone was more potent than cyclosporin A at inhibiting Ca2؉-induced permeability transition pore (PTP) opening in digitonin-permeabilized cells energized with succinate
We have shown that the PTP is modulated by electron flux through the respiratory chain complex I, the degree of control exerted by this process on the overall probability of pore opening is more relevant in skeletal muscle than in liver [28]
Summary
Studies over the past few years have led to the recognition that, in addition to their established role in energy metabolism, mitochondria are main actors of cell death (see Refs. 1 and 2 for recent reviews). Mitochondrial proapoptotic factors such as cytochrome c, apoptosis-inducing factor, and smac/diablo are normally confined to the mitochondrial intermembrane space. Involvement of the PTP in the commitment to cell death is supported by a large body of evidence based on the protective effect of two PTP inhibitors, namely cyclosporin A (CsA) We have shown that the PTP is modulated by electron flux through the respiratory chain complex I, the degree of control exerted by this process on the overall probability of pore opening is more relevant in skeletal muscle than in liver [28]. We show that rotenone dramatically inhibits PTP opening both in permeabilized and intact cells and that like CsA it prevents PTP opening-related cell death in these two cell lines
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