The mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury

doi:10.1016/j.yjmcc.2014.08.018

Journal of Molecular and Cellular Cardiology

Volume 78, January 2015, Pages 129-141

https://doi.org/10.1016/j.yjmcc.2014.08.018 Get rights and content

Highlights

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Proposals for the molecular identity of the MPTP are critically reviewed.
•
Contact sites (CS) between the inner and outer membranes regulate MPTP opening.
•
MPTP inhibition protects hearts from ischaemia/reperfusion (I/R) injury.
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Hexokinase 2 (HK2), which stabilises CS, dissociates from mitochondria in ischaemia.
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Preconditioning protects against I/R by preventing HK2 dissociation and MPTP opening.

Abstract

The mitochondrial permeability transition pore (MPTP) is a non-specific pore that opens in the inner mitochondrial membrane (IMM) when matrix [Ca²⁺] 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 [Ca²⁺] 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".

Introduction

The major role of mitochondria in the heart is the provision of ATP by oxidative phosphorylation to drive the contractile cycle and maintain ionic homeostasis. Oxidative phosphorylation requires the permeability barrier of the inner mitochondrial membrane (IMM) to be maintained. However, mammalian mitochondria contain a latent non-specific pore within their inner membrane, known as the mitochondrial permeability transition pore (MPTP). Opening of the MPTP not only prevents mitochondria from synthesising ATP by oxidative phosphorylation, but also allows reversal of the FoF1 ATP synthase causing hydrolysis of the ATP produced by glycolysis or any remaining “healthy” mitochondria [1]. If this occurs for any length of time, cells become depleted of ATP and will eventually die by necrosis. In essence, MPTP opening converts mitochondria from ATP providers that energise the cell to agents of cell death, akin to the caring Dr Jekyll turning into the murderous Mr Hyde [2]. It is now widely accepted that the MPTP plays a major role in determining the extent of injury the heart suffers during reperfusion after a prolonged period of ischaemia; such ischaemia/reperfusion injury (I/R) is reflected in the size of the necrotic area or infarct (see [2], [3], [4]). In this article we will first review what is currently known about the mechanism and molecular identity of the MPTP, paying particular attention to significant new developments since our previous review in this journal [1]. We will then briefly summarise the evidence that MPTP opening is a key event in I/R injury and finally review how inhibiting MPTP opening during reperfusion is cardioprotective.

Section snippets

Historical perspective

It has been known for more than sixty years that mitochondria become leaky, uncoupled and massively swollen if they are exposed to high calcium concentrations, especially in the presence of phosphate and when accompanied by oxidative stress (see [2], [5]). This phenomenon became known as the permeability transition and was originally thought to reflect activation of endogenous phospholipase A₂ leading to phospholipid breakdown within the IMM [6]. However, seminal studies in the late seventies

The molecular identity of the MPTP

Although the exact molecular identity of the MPTP is yet to be determined, several proteins have been implicated in its formation and regulation. Here we will critically review the evidence for the involvement of each of these proteins, focussing especially on recent papers proposing a role for the FoF1 ATP synthase [49], [50], [51], [52]. For a more detailed account of the evidence for the role of the adenine nucleotide translocase (ANT) and phosphate carrier (PiC) the reader is referred to

The role of the MPTP in ischaemia/reperfusion injury

It is now widely accepted that mitochondrial dysfunction, and particularly MPTP opening, plays a major role in determining the extent of injury the heart suffers during reperfusion after a prolonged period of ischaemia. This has been well reviewed elsewhere [2], [4], [21], [125] and only a brief summary will be given here. First, the conditions that occur following ischaemia and reperfusion are exactly those that would induce MPTP opening. In particular, the heart experiences calcium overload,

Inhibiting the MPTP is cardioprotective

As noted above, inhibitors of MPTP opening such as CsA and SfA provide protection from reperfusion injury in a variety of experimental models including those relevant to the clinical setting. Thus, using the Langendorff perfused rat heart, Hausenloy and colleagues demonstrated that reduction of infarct size is observed when CsA is added during the first 15 min of reperfusion [138]. Protection has also been observed using in vivo mouse and rabbit models of reperfusion injury [130], [131]

Conclusions and future directions

The central role of MPTP opening in causing reperfusion injury appears well established as is the cardioprotection offered by its inhibition. Indeed, pharmacological interventions targeting CyP-D have been proven effective in a wide range of models [2], [21], [194], [195] including a small proof of principle clinical trial [140]. Nevertheless, the effects are modest and not observed in all species [139], [194]. One reason for this may be that CyP-D only facilitates MPTP opening which can occur

Disclosures

None.

Acknowledgements

We would like to thank the many colleagues who have contributed to the research we have presented in this article that was performed in our own laboratory over many years. We are also extremely grateful for continuous funding of our research by the British Heart Foundation.

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Review articleThe mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury

Highlights

Abstract

Introduction

Section snippets

Historical perspective

The molecular identity of the MPTP

The role of the MPTP in ischaemia/reperfusion injury

Inhibiting the MPTP is cardioprotective

Conclusions and future directions

Disclosures

Acknowledgements

J Mol Cell Cardiol

Biochim Biophys Acta

Arch Biochem Biophys

Arch Biochem Biophys

J Biol Chem

J Biol Chem

J Biol Chem

Biochimie

J Biol Chem

Cell Calcium

J Biol Chem

Arch Biochem Biophys

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

Cell

Biochim Biophys Acta

Biophys J

J Biol Chem

J Mol Cell Cardiol

J Biol Chem

FEBS Lett

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

FEBS Lett

FEBS Lett

J Biol Chem

Biochim Biophys Acta

FEBS Lett

J Biol Chem

J Biol Chem

Mitochondrion

FEBS Lett

FEBS Lett

Biophys J

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Biochem Soc Trans

The mitochondrial permeability transition pore as a target for preconditioning and postconditioning

Basic Res Cardiol

The mitochondrial permeability transition pore: a mystery solved?

Front Physiol

Mechanisms by which mitochondria transport calcium

Am J Physiol

The reversible Ca2+-induced permeabilisation of rat liver mitochondria

Biochem J

Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress

Biochem J

Inhibition of Ca2+-induced large amplitude swelling of liver and heart mitochondria by Cyclosporin A is probably caused by the inhibitor binding to mitochondrial matrix peptidyl-prolyl cis–trans isomerase and preventing it interacting with the adenine nucleotide translocase

Biochem J

Review article
The mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury

The reversible Ca²⁺-induced permeabilisation of rat liver mitochondria

Inhibition by cyclosporin A of a Ca²⁺-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress

Inhibition of Ca²⁺-induced large amplitude swelling of liver and heart mitochondria by Cyclosporin A is probably caused by the inhibitor binding to mitochondrial matrix peptidyl-prolyl cis–trans isomerase and preventing it interacting with the adenine nucleotide translocase