Mitochondrial permeability transition

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Overview

Mitochondrial permeability transition, or MPT, is an increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Daltons in molecular weight. MPT results from opening of mitochondrial permeability transition pores, also known as the MPT pores or MPTP. The MPT pore is a protein pore that is formed in the membranes of mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Induction of the permeability transition pore can lead to mitochondrial swelling and cell death and plays an important role in some types of apoptosis.

The MPTP was proposed by Haworth and Hunter in 1979 and has since been found to be involved in, among other things, neurodegeneration, a process that results in damage and death of neurons.[1]

MPT is frequently studied in liver cells, which have especially large numbers of mitochondria.

Roles in pathology

MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium entry into the cell.[2][3][4] MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.[5] 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,[6] 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.[7] MPT may also play a role in mitochondrial autophagy.[7] Cells exposed to toxic amounts of Ca2+ ionophores also undergo MPT and death by necrosis.[7]

MPTP Structure

The MPT pore is a nonselective, high conductance channel with multiple macromolecular components.[8][9] It forms at sites where the inner and outer membranes of the mitochondria meet.[10] Though the exact structure of the MPTP is still unknown, several proteins probably come together to form the pore, including adenine nucleotide translocase (ANT), the mitochondrial inner membrane protein transporter (Tim), the protein transporter at the outer membrane (Tom), the outer membrane voltage-dependent anion channel (VDAC) and cyclophilin-D.[11] Cyclosporin A blocks the formation of the MPT pore by interacting with cyclophilin from the mitochondrial matrix and preventing its joining the pore.[12] 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.[13] However, the cells do die in response to stimuli that kill cells through apoptosis, suggesting that MPT does not control cell death by apoptosis.[13]

MPTP blockers

Agents that block MPT include the immune suppressant cyclosporin A (CsA); N-methyl-Val-4-cyclosporin A (MeValCsA), a non-immunosuppressant derivative of CsA; another non-immunosuppressive agent, NIM811, 2-aminoethoxydiphenyl borate (2-APB)[14], and bongkrekic acid.

Factors in MPT induction

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.[15][16] This is possibly because Ca2+ binds to and activates Ca2+ binding sites on the matrix side of the MPTP.[9][17] MPT induction is also due to the dissipation of the difference in voltage between the inside and outside of mitochondrial membranes (known as permeability transition, or δψ).[3][18] The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.[11][19]

Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids,[20] and inorganic phosphate.[21] However, these factors cannot open the pore without Ca2+, though at high enough concentrations, Ca2+ alone can induce MPT.[22]

Stress in the endoplasmic reticulum can be a factor in triggering MPT.[23]

Things that cause the pore to close or remain closed include acidic conditions,[24] high concentrations of ADP,[19][25] high concentrations of ATP,[26] and high concentrations of NADH.[16] Divalent cations like Mg2+ also inhibit MPT, because they can compete with Ca2+ for the Ca2+ binding sites on the matrix side of the MPTP.[9]

Effects of MPT

Multiple studies have found the MPT to be a key factor in the damage to neurons caused by excitotoxicity.[3][4][17]

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 IMM uninhibited.[3][4] Loss of Δψ interferes with the production of adenosine triphosphate (ATP), the cell's main source of energy, because mitochondria must have an electrochemical gradient to provide the driving force for ATP production.

In cell damage resulting from conditions such as neurodegenerative diseases and head injury, opening of the mitochondrial permeability transition pore can greatly reduce ATP production, and can cause ATP synthase to begin hydrolysing, rather than producing, ATP.[27] This produces an energy deficit in the cell, just when it most needs ATP to fuel activity of ion pumps such as the Na+/Ca2+ exchanger, which must be activated more than under normal conditions in order to rid the cell of excess calcium.

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 electron transport chain (ETC), such as cytochrome c, through the MPTP.[28] 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.[29] This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochrome c.[29] Cytochrome c can in turn cause the cell to go through apoptosis ("commit suicide") by activating pro-apoptotic factors. Other researchers contend that it is not mitochondrial membrane rupture that leads to cytochrome c release, but rather another mechanism, such as translocation of the molecule through channels in the outer membrane, which does not involve the MPTP.[30]

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.[5]

Possible evolutionary purpose of the MPTP

The existence of a pore that causes cell death has led to speculation about its possible evolutionary benefit. Some have speculated that the MPT pore may minimize injury by causing badly injured cells to die quickly and by preventing cells from oxidizing substances that could be used elsewhere.[31]

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[17] and would allow certain molecules and ions to cross the mitochondrial membranes. The low-conductance state may allow small molecules like Ca2+ to leave mitochondria quickly, in order to aid in the cycling of Ca2+ in healthy cells.[32][25] If this is the case, MPT may be a harmful side effect of abnormal activity of a usually beneficial MPTP.

See also

References

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