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The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell
1C.N.R. Unit for the Study of Biomembranes, University of Padua Medical School, Italy.
Abstract:
The permeability transition pore (MTP) is a high conductance channel of the mitochondrial inner membrane inhibited by cyclosporin A. While the physiological role of the MTP has not been clarified yet, it is becoming clear that this channel plays an important role in the pathways leading to cell death. The recent demonstrations that the MTP is controlled by the membrane potential, that a variety of physiological and pathological effectors can modulate the threshold voltage at which pore opening occurs, and that surface potential may contribute to pore modulation provide a useful framework to describe the mechanistic aspects of pore function in isolated mitochondria. Here we (i) briefly review the key features of pore regulation, and report our recent progress on the role of oxidants and mitochondrial cyclophilin; and (ii) elaborate on how MTP regulation by cellular pathophysiological effectors (such as cytosolic [Ca2+] transients, oxidative stress, and changes in the concentration of polyamines, nitric oxide, and metabolites of both the sphingomyelin and phospholipase A2 pathways) might take place in vivo. Further definition of the MTP checkpoints should help in the design of specific modulators, and offers great promise for the development of new conceptual and pharmacological tools aimed at therapeutic intervention in pathological conditions where pore opening is a critical event.
Insights
The mitochondrial permeability transition pore (MTP) regulates cell death pathways. Understanding its control by membrane potential and cellular factors is key for developing new therapeutic interventions.
Area of Science:
- Mitochondrial biology
- Cell death pathways
- Membrane biophysics
Background:
- The mitochondrial permeability transition pore (MTP) is a channel in the inner mitochondrial membrane.
- Cyclosporin A inhibits MTP, and it is implicated in cell death.
- MTP regulation by membrane potential and surface potential is crucial for its function.
Purpose of the Study:
- To review MTP regulation mechanisms.
- To present progress on the role of oxidants and mitochondrial cyclophilin in MTP function.
- To elaborate on in vivo MTP regulation by cellular pathophysiological effectors.
Main Methods:
- Review of existing literature on MTP regulation.
- Reporting of recent experimental progress on oxidants and mitochondrial cyclophilin.
- Elaboration on in vivo mechanisms of MTP regulation by cellular effectors.
Main Results:
- MTP is controlled by membrane potential, with varying thresholds for opening.
- Physiological and pathological effectors modulate MTP opening.
- Cellular factors like Ca2+, oxidative stress, and metabolites influence MTP regulation in vivo.
Conclusions:
- Further defining MTP checkpoints is essential for designing specific modulators.
- Understanding MTP regulation offers promise for therapeutic interventions in diseases involving MTP opening.
- MTP plays a critical role in cell death pathways, making it a potential therapeutic target.