Themitochondrial permeability transition pore (mPTP orMPTP; also referred to asPTP,mTP, orMTP) is a protein pore complex that forms in theinner mitochondrial membrane under certain pathological conditions such astraumatic brain injury,ischemia, andstroke. Opening of the pore causes an increase in the permeability of the mitochondrial membrane to solutes with a molecular mass less than 1,500daltons, leading to loss of membrane potential, swelling of the organelle, rupture of the outer membrane, and eventual cell death.

The mPTP is thought to be regulated by multiple mitochondrial proteins. Historically,Cyclophilin D and theTSPO (formerly the peripheral benzodiazepine receptor) have been considered central components. In 2025, the AAA+ ATPase proteinATAD3A was identified as a novel upstream regulator of mPTP opening. Loss of ATAD3A was shown to prevent calcium-induced pore formation and render mitochondria insensitive tocyclosporin A, suggesting it acts upstream of Cyclophilin D and is essential for permeability transition under stress.^[1]

The MPTP was originally discovered by Haworth and Hunter^[2] in 1979 and has been found to be involved inneurodegeneration, hepatotoxicity from Reye-related agents, cardiac necrosis and nervous and muscular dystrophies among other deleterious events inducing cell damage and death.^[3][4][5][6]

MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in neuronal cell death inexcitotoxicity, in which overactivation ofglutamate receptors causes excessive calcium entry into thecell.^[7][8][9] MPT also appears to play a key role in damage caused byischemia, as occurs in aheart attack andstroke.^[10] However, research has shown that the MPT pore remains closed during ischemia, but opens once the tissues arereperfused with blood after the ischemic period,^[11] playing a role inreperfusion injury.

MPT is also thought to underlie the cell death induced byReye's syndrome, since chemicals that can cause the syndrome, likesalicylate andvalproate, cause MPT.^[12] MPT may also play a role in mitochondrialautophagy.^[12] Cells exposed to toxic amounts of Ca²⁺ionophores also undergo MPT and death by necrosis.^[12]

While the MPT modulation has been widely studied, little is known about its structure. Initial experiments by Szabó and Zoratti proposed the MPT may compriseVoltage Dependent Anion Channel (VDAC) molecules. Nevertheless, this hypothesis was shown to be incorrect as VDAC^−/− mitochondria were still capable to undergo MPT.^[13][14]

Further hypothesis by Halestrap's group convincingly suggested the MPT was formed by the inner membraneAdenine Nucleotide Translocase (ANT), but genetic ablation of such protein still led to MPT onset.^[15][16]

Thus, the only MPTP components identified so far are theTSPO (previously known as the peripheral benzodiazepine receptor) located in the mitochondrial outer membrane andcyclophilin-D in themitochondrial matrix.^[17][18]

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.^[19]

However, these cells do die in response to stimuli that kill cells through apoptosis, suggesting that MPT does not control cell death by apoptosis.^[19] Recent findings have identified ATAD3A, an inner mitochondrial membrane AAA+ ATPase, as a critical upstream modulator of mPTP formation, acting via regulation of mitochondrial cholesterol transport and cyclophilin D localization.^[20]

Various factors enhance the likelihood of MPTP opening. In some mitochondria, such as those in thecentral nervous system, high levels of Ca²⁺ within mitochondria can cause the MPT pore to open.^[21][22] This is possibly because Ca²⁺ binds to and activates Ca²⁺ binding sites on the matrix side of the MPTP.^[7]MPT induction is also due to the dissipation of the difference involtage across the inner mitochondrial membrane (known as transmembrane potential, or Δψ).In neurons and astrocytes, the contribution of membrane potential to MPT induction is complex, see.^[23]The presence offree radicals, another result of excessive intracellular calciumconcentrations, can also cause the MPT pore to open.^[24]

Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids,^[25] and inorganic phosphate.^[26] However, these factors cannot open the pore without Ca²⁺, though at high enough concentrations, Ca²⁺ alone can induce MPT.^[27]

Stress in theendoplasmic reticulum can be a factor in triggering MPT.^[28]

Conditions that cause the pore to close or remain closed includeacidic conditions,^[29] high concentrations ofADP,^[24][30] high concentrations ofATP,^[31] and high concentrations ofNADH. Divalentcations likeMg²⁺ also inhibit MPT, because they can compete with Ca²⁺ for the Ca²⁺ binding sites on the matrix and/or cytoplasmic side of the MPTP.^[23]

Multiple studies have found the MPT to be a key factor in the damage to neurons caused byexcitotoxicity.^[7][8][9]

The induction of MPT, which increases mitochondrial membrane permeability, causes mitochondria to become further depolarized, meaning that Δψ is abolished. When Δψ is lost,protons and some molecules are able to flow across the outer mitochondrial membrane uninhibited.^[8][9]Loss of Δψ interferes with the production ofadenosine triphosphate (ATP), the cell's main source of energy, because mitochondria must have anelectrochemical gradient to provide the driving force for ATP production.

In cell damage resulting from conditions such asneurodegenerative diseases andhead injury, opening of the mitochondrial permeability transition pore can greatly reduce ATP production, and can causeATP synthase to beginhydrolysing, rather than producing, ATP.^[32] This produces an energy deficit in the cell, just when it most needs ATP to fuel activity ofion pumps.

MPT also allows Ca²⁺ to leave the mitochondrion, which can place further stress on nearby mitochondria, and which can activate harmful calcium-dependentproteases such ascalpain.

Reactive oxygen species (ROS) are also produced as a result of opening the MPT pore. MPT can allowantioxidant molecules such asglutathione to exit mitochondria, reducing the organelles' ability to neutralize ROS. In addition, theelectron transport chain (ETC) may produce more free radicals due to loss of components of the ETC, such ascytochromec, through the MPTP.^[33] 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'sosmolar load.^[34] This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochromec.^[34] Cytochromec can in turn cause the cell to go throughapoptosis ("commit suicide") by activating pro-apoptotic factors. Other researchers contend that it is not mitochondrial membrane rupture that leads to cytochromec release, but rather another mechanism, such as translocation of the molecule through channels in the outer membrane, which does not involve the MPTP.^[35]

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 undergonecrotic cell death.^[10]

Although the MPTP has been studied mainly in mitochondria from mammalian sources, mitochondria from diverse species also undergo a similar transition.^[36] 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.^[37] Under severe stress/pathologic conditions, MPTP opening would trigger injured cell death mainly through necrosis.^[38]

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^[7] and would allow certain molecules and ions to cross the mitochondrial membranes. The low-conductance state may allow small ions like Ca²⁺ to leave mitochondria quickly, in order to aid in the cycling of Ca²⁺ in healthy cells.^[30][39] 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,^[40] yeasts, such asSaccharomyces cerevisiae,^[41] birds, such as guinea fowl^[42] and primitive vertebrates such as the Balticlamprey.^[43] 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^[44] strongly suggesting this event may be a conserved characteristic throughout the eukaryotic domain.^[45]

• Crista
• NMDA receptor
• NMDA receptor antagonist

• Mitochondrial permeability transition pore: an enigmatic gatekeeper (2012) NHS&T, Vol 1(3):47-51
• Mitochondrial Permeability Transition (PT) from Celldeath.de. Accessed January 1, 2007.
• Bernardi, P; Di Lisa, F (2015)."The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection".Journal of Molecular and Cellular Cardiology.78:100–106.doi:10.1016/j.yjmcc.2014.09.023.PMC 4294587.PMID 25268651.
• mitochondrial+permeability+transition+pore at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Cellular respiration
• Neurotrauma
• Mitochondria

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