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Protein
The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Opening allows increase in the permeability of the mitochondrial membranes to molecules of less than 1500 daltons in molecular weight. Induction of the permeability transition pore, mitochondrial membrane permeability transition (mPT or MPT), can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

The MPTP was originally discovered by Haworth and Hunter in 1979 and has been found to be involved in neurodegeneration, hepatotoxicity from Reye related agents, cardiac necrosis and nervous and muscular dystrophies among other deleterious events inducing cell damage and death. MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in neuronal cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium entry into the cell. MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke. However, research has shown that the MPT pore remains closed during ischemia, but opens once the tissues are reperfused with blood after the ischemic period, playing a role in reperfusion injury. MPT is also thought to underlie the cell death induced by Reye's syndrome, since chemicals that can cause the syndrome, like salicylate and valproate, cause MPT. MPT may also play a role in mitochondrial autophagy. Further hypothesis by Halestrap's group convincingly suggested the MPT was formed by the inner membrane Adenine Nucleotide Translocase (ANT), but genetic ablation of such protein still led to MPT onset. Thus, the only MPTP components identified so far are the TSPO (previously known as the peripheral benzodiazepine receptor) located in the mitochondrial outer membrane and cyclophilin D in the mitochondrial matrix. Mice lacking the gene for cyclophilin D develop normally, but their cells do not undergo Cyclosporin A sensitive MPT, and they are resistant to necrotic death from ischemia or overload of Ca2+ or free radicals. However, these cells do die in response to stimuli that kill cells through apoptosis, suggesting that MPT does not control cell death by apoptosis. bongkrekic acid and alisporivir (also known as Debio 025). TRO40303 is a newly synthetitised MPT blocker developed by Trophos company and currently is in Phase I clinical trial.

Various factors enhance the likelihood of MPTP opening. In some mitochondria, such as those in the central nervous system, high levels of Ca2+ within mitochondria can cause the MPT pore to open. This is possibly because Ca2+ binds to and activates Ca2+ binding sites on the matrix side of the MPTP. The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open. Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids, and inorganic phosphate. However, these factors cannot open the pore without Ca2+, though at high enough concentrations, Ca2+ alone can induce MPT. Stress in the endoplasmic reticulum can be a factor in triggering MPT. Conditions that cause the pore to close or remain closed include acidic conditions, high concentrations of ADP, and high concentrations of NADH. Divalent cations like Mg2+ also inhibit MPT, because they can compete with Ca2+ for the Ca2+ binding sites on the matrix and/or cytoplasmic side of the MPTP. This produces an energy deficit in the cell, just when it most needs ATP to fuel activity of ion pumps. MPT also allows Ca2+ to leave the mitochondrion, which can place further stress on nearby mitochondria, and which can activate harmful calcium dependent proteases such as calpain. Reactive oxygen species (ROS) are also produced as a result of opening the MPT pore. MPT can allow antioxidant molecules such as glutathione to exit mitochondria, reducing the organelles' ability to neutralize ROS. In addition, the electron transport chain (ETC) may produce more free radicals due to loss of components of the ETC, such as cytochrome c, through the MPTP. Loss of ETC components can lead to escape of electrons from the chain, which can then reduce molecules and form free radicals. MPT causes mitochondria to become permeable to molecules smaller than 1.5 kDa, which, once inside, draw water in by increasing the organelle's osmolar load. This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochrome c.

Much research has found that the fate of the cell after an insult depends on the extent of MPT. If MPT occurs to only a slight extent, the cell may recover, whereas if it occurs more it may undergo apoptosis. If it occurs to an even larger degree the cell is likely to undergo necrotic cell death. While its occurrence can be easily detected, its purpose still remains elusive. Some have speculated that the regulated opening of the MPT pore may minimize cell injury by causing ROS producing mitochondria to undergo selective lysosome dependent mitophagy during nutrient starvation conditions. Under severe stress/pathologic conditions, MPTP opening would trigger injured cell death mainly through necrosis. There is controversy about the question of whether the MPTP is able to exist in a harmless, "low conductance" state. This low conductance state would not induce MPT If this is the case, MPT may be a harmful side effect of abnormal activity of a usually beneficial MPTP. MPTP has been detected in mitochondria from plants, yeasts, such as Saccharomyces cerevisiae, birds, such as guinea fowl and primitive vertebrates such as the Baltic lamprey. While the permeability transition is evident in mitochondria from these sources, its sensitivity to its classic modulators may differ when compared with mammalian mitochondria. Nevertheless, CsA insensitive MPTP can be triggered in mammalian mitochondria given appropriate experimental conditions strongly suggesting this event may be a conserved characteristic throughout the eukaryotic domain.