Mitochondrial permeability transition pore
Encyclopedia
The Mitochondrial Permeability Transition, or MPT, is defined as an increase in the permeability of the mitochondrial membranes to molecule
s of less than 1500 Dalton
s in molecular weight. MPT results from the opening of a mitochondrial permeability transition pore, also known as the MPT pore or MPTP. The MPT pore is a protein
pore that is formed in the inner membrane of the 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 through apoptosis or necrosis depending on the particular biological setting .
, hepatotoxicity from Reye-related agents, cardiac necrosis 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 receptor
s 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+ ionophore
s also undergo MPT and death by necrosis.
-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.
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), and bongkrekic acid.
, 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 .
MPT induction is also due to the dissipation of the difference in voltage
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.
The presence of free radicals, another result of excessive intracellular calcium concentration
s, 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 acid
ic conditions, high concentrations of ADP
, high concentrations of ATP
, 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 .
.
The induction of MPT, which increases mitochondrial membrane permeability, causes mitochondria to become further depolarized, meaning that Δψ is abolished. When Δψ is lost, proton
s and some molecules are able to flow across the outer mitochondrial membrane uninhibited.
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. 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 protease
s 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. 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. 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.
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
.
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s of less than 1500 Dalton
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
s in molecular weight. MPT results from the opening of a mitochondrial permeability transition pore, also known as the MPT pore or MPTP. The MPT pore is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
pore that is formed in the inner membrane of the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
under certain pathological conditions such as traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. Induction of the permeability transition pore can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting .
Roles in pathology
The MPTP was originally discovered by Haworth and Hunter in 1979 and has been found to be involved in neurodegenerationNeurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
, hepatotoxicity from Reye-related agents, cardiac necrosis 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
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, in which overactivation of glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s causes excessive calcium entry into the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. MPT also appears to play a key role in damage caused by ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, as occurs in a heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. 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
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...
.
MPT is also thought to underlie the cell death induced by Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
, since chemicals that can cause the syndrome, like salicylate and valproate, cause MPT. MPT may also play a role in mitochondrial autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
. Cells exposed to toxic amounts of Ca2+ ionophore
Ionophore
An ionophore is a lipid-soluble molecule usually synthesized by microorganisms to transport ions across the lipid bilayer of the cell membrane...
s also undergo MPT and death by necrosis.
MPTP Structure
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 cyclophilinCyclophilin
Cyclophilins are a family of proteins from vertebrates and other organisms that bind to cyclosporine, an immunosuppressant which is usually used to suppress rejection after internal organ transplants...
-D in the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
. . 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.
MPTP blockers
Agents that transiently block MPT include the immuneImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
suppressant cyclosporin A (CsA); N-methyl-Val-4-cyclosporin A (MeValCsA), a non-immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
derivative of CsA; another non-immunosuppressive agent, NIM811
NIM811
NIM811 is a mitochondrial permeability transition inhibitor. Also known as N-methyl-4-isoleucine cyclosporin, it is a four-substituted cyclosporine that does not bind to cyclophilin A and therefore lacks immunosuppressive activity. Rather, NIM811 binds and inhibits cyclophilin....
, 2-aminoethoxydiphenyl borate (2-APB), 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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, 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 .
MPT induction is also due to the dissipation of the difference in voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
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.
The presence of free radicals, another result of excessive intracellular calcium concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s, 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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
can be a factor in triggering MPT.
Conditions that cause the pore to close or remain closed include acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic conditions, high concentrations of ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, high concentrations of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, and high concentrations of NADH
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
. Divalent cations like Mg2+
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
also inhibit MPT, because they can compete with Ca2+ for the Ca2+ binding sites on the matrix and/or cytoplasmic side of the MPTP .
Effects of MPT
Multiple studies have found the MPT to be a key factor in the damage to neurons caused by excitotoxicityExcitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
.
The induction of MPT, which increases mitochondrial membrane permeability, causes mitochondria to become further depolarized, meaning that Δψ is abolished. When Δψ is lost, proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
s and some molecules are able to flow across the outer mitochondrial membrane uninhibited.
Loss of Δψ interferes with the production of adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP), the cell's main source of energy, because mitochondria must have an electrochemical gradient
Electrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH gradient...
to provide the driving force for ATP production.
In cell damage resulting from conditions such as neurodegenerative diseases and head injury
Head injury
Head injury refers to trauma of the head. This may or may not include injury to the brain. However, the terms traumatic brain injury and head injury are often used interchangeably in medical literature....
, opening of the mitochondrial permeability transition pore can greatly reduce ATP production, and can cause ATP synthase
ATP synthase
right|thumb|300px|Molecular model of ATP synthase by X-ray diffraction methodATP synthase is an important enzyme that provides energy for the cell to use through the synthesis of adenosine triphosphate . ATP is the most commonly used "energy currency" of cells from most organisms...
to begin hydrolysing
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
, rather than producing, ATP. 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 protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s such as calpain
Calpain
A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database...
.
Reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) are also produced as a result of opening the MPT pore. MPT can allow antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
molecules such as glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
to exit mitochondria, reducing the organelles' ability to neutralize ROS. In addition, the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
(ETC) may produce more free radicals due to loss of components of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
(ETC), such as cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
, 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
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
. This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochrome c. Cytochrome c can in turn cause the cell to go through apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
("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.
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
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
.
Possible evolutionary purpose of the MPTP
Despite the MPTP has been studied mainly in mitochondria from mammalian sources, mitochondria from diverse kingdoms also undergo a similar transition . 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 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. 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 and invertebrates 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.External links
- Mitochondrial Permeability Transition (PT) from Celldeath.de. Accessed January 1, 2007.