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Mitochondrial permeability transition pore
The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP, or MTP) is a protein pore complex that forms in the inner mitochondrial membrane under certain pathological conditions such as traumatic brain injury, ischemia, and stroke. Opening of the pore causes an increase in the permeability of the mitochondrial membrane to solutes with a molecular mass less than 1,500 daltons, 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 the TSPO (formerly the peripheral benzodiazepine receptor) have been considered central components. In 2025, the AAA+ ATPase protein ATAD3A 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 to cyclosporin A, suggesting it acts upstream of Cyclophilin D and is essential for permeability transition under stress.
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. Cells exposed to toxic amounts of Ca2+ ionophores also undergo MPT and death by necrosis.
While the MPT modulation has been widely studied, little is known about its structure. Initial experiments by Szabó and Zoratti proposed the MPT may comprise Voltage Dependent Anion Channel (VDAC) molecules. Nevertheless, this hypothesis was shown to be incorrect as VDAC−/− mitochondria were still capable to undergo MPT.
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.
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Mitochondrial permeability transition pore AI simulator
(@Mitochondrial permeability transition pore_simulator)
Mitochondrial permeability transition pore
The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP, or MTP) is a protein pore complex that forms in the inner mitochondrial membrane under certain pathological conditions such as traumatic brain injury, ischemia, and stroke. Opening of the pore causes an increase in the permeability of the mitochondrial membrane to solutes with a molecular mass less than 1,500 daltons, 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 the TSPO (formerly the peripheral benzodiazepine receptor) have been considered central components. In 2025, the AAA+ ATPase protein ATAD3A 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 to cyclosporin A, suggesting it acts upstream of Cyclophilin D and is essential for permeability transition under stress.
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. Cells exposed to toxic amounts of Ca2+ ionophores also undergo MPT and death by necrosis.
While the MPT modulation has been widely studied, little is known about its structure. Initial experiments by Szabó and Zoratti proposed the MPT may comprise Voltage Dependent Anion Channel (VDAC) molecules. Nevertheless, this hypothesis was shown to be incorrect as VDAC−/− mitochondria were still capable to undergo MPT.
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.