[1] The MPTP was originally discovered by Haworth and Hunter[2] 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.
[6][7][8] MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.
Initial experiments by Szabó and Zoratti proposed the MPT may comprise Voltage Dependent Anion Channel (VDAC) molecules.
[16][17] 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.
[23] The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.
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.
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.
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.
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.
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.
MPTP has been detected in mitochondria from plants,[40] yeasts, such as Saccharomyces cerevisiae,[41] birds, such as guinea fowl[42] and primitive vertebrates such as the Baltic lamprey.
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.