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Updated: Apr 24, 2026
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion
Andrew P Halestrap1, Andrew P Richardson1
1School of Biochemistry and Bristol CardioVascular, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
Abstract:
The mitochondrial permeability transition pore (MPTP) is a non-specific pore that opens in the inner mitochondrial membrane (IMM) when matrix [Ca(2+)] is high, especially when accompanied by oxidative stress, high [Pi] and adenine nucleotide depletion. Such conditions occur during ischaemia and subsequent reperfusion, when MPTP opening is known to occur and cause irreversible damage to the heart. Matrix cyclophilin D facilitates MPTP opening and is the target of its inhibition by cyclosporin A that is cardioprotective. Less certainty exists over the composition of the pore itself, with structural and/or regulatory roles proposed for the adenine nucleotide translocase, the phosphate carrier and the FoF1 ATP synthase. Here we critically review the supporting data for the role of each and suggest that they may interact with each other through their bound cardiolipin to form the ATP synthasome. We propose that under conditions favouring MPTP opening, calcium-triggered conformational changes in these proteins may perturb the interface between them generating the pore. Proteins associated with the outer mitochondrial membrane (OMM), such as members of the Bcl-2 family and hexokinase (HK), whilst not directly involved in pore formation, may regulate MPTP opening through interactions between OMM and IMM proteins at "contact sites". Recent evidence suggests that cardioprotective protocols such as preconditioning inhibit MPTP opening at reperfusion by preventing the loss of mitochondrial bound HK2 that stabilises these contact sites. Contact site breakage both sensitises the MPTP to [Ca(2+)] and facilitates cytochrome c loss from the intermembrane space leading to greater ROS production and further MPTP opening. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".
Insights
The mitochondrial permeability transition pore (MPTP) opening during heart reperfusion causes damage. Cyclophilin D and interactions between IMM proteins like ATP synthase at contact sites regulate MPTP, offering cardioprotection targets.
Area of Science:
- Mitochondrial Biology
- Cardiovascular Pathophysiology
- Cellular Signaling
Background:
- The mitochondrial permeability transition pore (MPTP) opens in the inner mitochondrial membrane (IMM) under stress conditions like ischemia-reperfusion.
- MPTP opening leads to irreversible heart damage, with matrix cyclophilin D identified as a key facilitator and target for cardioprotection (e.g., cyclosporin A).
- The precise composition of the MPTP remains uncertain, with proposed roles for IMM proteins including adenine nucleotide translocase, phosphate carrier, and FoF1 ATP synthase.
Purpose of the Study:
- To critically review the evidence for the roles of IMM proteins in MPTP formation.
- To propose a model where IMM proteins interact via cardiolipin to form the ATP synthasome, with calcium-induced conformational changes generating the pore.
- To examine the regulatory role of outer mitochondrial membrane (OMM) proteins, such as Bcl-2 family members and hexokinase (HK), at OMM-IMM contact sites.
Main Methods:
- Critical review of existing scientific literature and supporting data.
- Analysis of proposed protein interactions and structural roles in MPTP formation.
- Evaluation of evidence linking OMM-IMM contact sites and their regulation to MPTP activity.
Main Results:
- Suggests IMM proteins (ANT, PiC, ATP synthase) may interact via cardiolipin to form the ATP synthasome, with calcium-induced conformational changes creating the MPTP.
- Highlights that OMM proteins (Bcl-2, HK) regulate MPTP opening at contact sites, not by forming the pore itself.
- Indicates that cardioprotective preconditioning inhibits MPTP opening by stabilizing mitochondrial-bound HK2 at contact sites, preventing sensitization to calcium and cytochrome c loss.
Conclusions:
- The MPTP likely forms from interactions between IMM proteins within the ATP synthasome, triggered by calcium.
- Regulation of MPTP opening involves OMM proteins at contact sites, with stabilization of these sites conferring cardioprotection.
- Understanding these mechanisms provides insights into mitigating heart damage during ischemia-reperfusion.
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