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Regulation of the mitochondrial permeability transition pore by ubiquinone analogs. A progress report
Ludivine Walter1, Hideto Miyoshi, Xavier Leverve
1Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France.
Abstract:
The permeability transition pore (PTP) is a mitochondrial inner membrane Ca2+-sensitive channel that plays a key role in different models of cell death. In a series of recent studies we have shown that the PTP is modulated by quinones, and we have identified three functional classes: (i) PTP inhibitors; (ii) PTP inducers; and (iii) PTP-inactive quinones that compete with both inhibitors and inducers. Here, we review our current understanding of pore regulation by quinones, and present the results obtained with a new series of structural variants. Based on the effects of the compounds studied so far, we confirm that minor structural changes profoundly modify the effects of quinones on the PTP. On the other hand, quinones with very different structural features may have qualitatively similar effects on the PTP. Taken together, these results support our original proposal that quinones affect the PTP through a common binding site whose occupancy modulates its open-closed transitions, possibly through secondary changes of the Ca2+-binding affinity.
Insights
Quinones regulate the mitochondrial permeability transition pore (PTP), a key channel in cell death. Minor structural changes significantly alter quinone effects, suggesting a common binding site influences PTP activity.
Area of Science:
- Mitochondrial biophysics
- Cellular signaling
- Pharmacology
Background:
- The permeability transition pore (PTP) is a critical Ca2+-sensitive channel in the inner mitochondrial membrane.
- PTP dysfunction is implicated in various cell death pathways.
- Quinones are known modulators of PTP activity.
Purpose of the Study:
- To review the current understanding of quinone regulation of the PTP.
- To investigate the effects of novel quinone structural variants on PTP activity.
- To elucidate the mechanism by which quinones interact with the PTP.
Main Methods:
- Synthesis and characterization of quinone structural variants.
- Assays to determine PTP inhibition, induction, or competitive binding.
- Analysis of structure-activity relationships for quinone-PTP interactions.
Main Results:
- Quinones were classified into inhibitors, inducers, and inactive competitors.
- Minor structural modifications of quinones led to significant alterations in PTP modulation.
- Structurally diverse quinones exhibited similar effects on PTP activity.
- Evidence supports a common quinone binding site on the PTP.
Conclusions:
- Quinone binding to a common site modulates PTP open-closed transitions.
- PTP regulation by quinones may involve alterations in Ca2+-binding affinity.
- Understanding quinone-PTP interactions offers insights into cell death mechanisms.