The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that is formed in the inner membrane of the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

under certain pathological conditions such as

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...

and

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

. Opening allows increase in the permeability of the

l membranes to

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

s of less than 1500

Dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit * John Dalton, chemist, physicist and meteorologist Entertainment * Dalton (Buffyverse), minor cha ...

s in molecular weight. Induction of the permeability transition pore, mitochondrial membrane permeability transition (mPT or MPT), can lead to mitochondrial swelling and

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

through

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

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

neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

, 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 excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

, in which overactivation of

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system a ...

s causes excessive calcium entry into the

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

. MPT also appears to play a key role in damage caused by

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

, as occurs in a

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...

and

. 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, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + '' perfusion'') after a period of ischemia or lack of oxygen (anoxia or h ...

. MPT is also thought to underlie the cell death induced by

Reye's syndrome Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usually d ...

, since chemicals that can cause the syndrome, like

salicylate Salicylic acid is an organic compound with the formula HOC6H4CO2H. A colorless, bitter-tasting solid, it is a precursor to and a metabolite of aspirin (acetylsalicylic acid). It is a plant hormone, and has been listed by the EPA Toxic Substance ...

and

valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

, cause MPT. MPT may also play a role in mitochondrial

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

. Cells exposed to toxic amounts of Ca²⁺

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...

s also undergo MPT and death by necrosis.

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

cyclophilin Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of lif ...

-D in the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

. 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

immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

suppressant

cyclosporin A Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...

(CsA); N-methyl-Val-4-cyclosporin A (MeValCsA), a non-

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

derivative of CsA; another non-immunosuppressive agent,

NIM811 NIM811 is a mitochondrial permeability transition inhibitor. Also known as ''N''-methyl-4-isoleucine cyclosporin, it is a four-substituted cyclosporine analogue that binds to cyclophilin, however this binary complex cannot bind to calcineurin, an ...

, 2-aminoethoxydiphenyl borate (2-APB),

bongkrekic acid Bongkrek acid (also known as bongkrekic acid) is a respiratory toxin produced in fermented coconut or corn contaminated by the bacterium ''Burkholderia gladioli'' pathovar ''cocovenenans''. It is highly toxic because the compound inhibits the ...

and alisporivir (also known as Debio-025). TRO40303 is a newly synthetitised MPT blocker developed by

Trophos Trophos was a biopharmaceutical company specialising in the discovery and development of novel therapeutics to treat both orphan Neurodegenerative diseases, neurodegenerative diseases and more prevalent disorders. Trophos was founded in 1999 in ...

company and currently is in

Phase I clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

Factors in MPT induction

Various factors enhance the likelihood of MPTP opening. In some mitochondria, such as those in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

, 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, also known as electric pressure, electric tension, or (electric) potential difference, is the difference in electric potential between two points. In a static electric field, it corresponds to the work needed per unit of charge to m ...

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 radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

s, another result of excessive intracellular calcium

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...

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 The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

can be a factor in triggering MPT. Conditions that cause the pore to close or remain closed include

acid In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...

ic conditions, high concentrations of ADP, high concentrations of ATP, and high concentrations of

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

. Divalent

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

s 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.

Effects

Multiple studies have found the MPT to be a key factor in the damage to neurons caused by

. 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 A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

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 (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...

(ATP), the cell's main source of energy, because mitochondria must have an

electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and th ...

to provide the driving force for ATP production. In cell damage resulting from conditions such as

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s and

head injury A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inju ...

, opening of the mitochondrial permeability transition pore can greatly reduce ATP production, and can cause

ATP synthase ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation ...

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 pump An ion pump (also referred to as a sputter ion pump) is a type of vacuum pump which operates by sputtering a metal getter. Under ideal conditions, ion pumps are capable of reaching pressures as low as 10−11 mbar. An ion pump first ionizes ga ...

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

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s such as

calpain A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (protease, proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of proteas ...

Reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(ROS) are also produced as a result of opening the MPT pore. MPT can allow

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...

molecules such as

glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...

to exit mitochondria, reducing the organelles' ability to neutralize ROS. In addition, the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

(ETC) may produce more free radicals due to loss of components of the 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

("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.

Possible evolutionary purpose

Although the MPTP has been studied mainly in mitochondria from mammalian sources, mitochondria from diverse species 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.Haworth RA and Hunter DR. 2001. Ca²⁺-induced transition in mitochondria: A cellular catastrophe? Chapter 6 In ''Mitochondria in pathogenesis''. Lemasters JJ and Nieminen AL, eds. Kluwer Academic/Plenum Publishers. New York. Pages 115 - 124. 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 ions 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'', birds, such as guinea fowl and primitive vertebrates such as the Baltic

lamprey Lampreys (sometimes inaccurately called lamprey eels) are an ancient extant lineage of jawless fish of the order Petromyzontiformes , placed in the superclass Cyclostomata. The adult lamprey may be characterized by a toothed, funnel-like s ...

. 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.

References

External links

Mitochondrial permeability transition pore: an enigmatic gatekeeper
(2012) NHS&T, Vol 1(3):47-51

from Celldeath.de. Accessed January 1, 2007. * * {{Mitochondrial proteins Cellular respiration Neurotrauma Mitochondria