Mitochondrial permeability transition

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. [Fiskum G. 2000. Mitochondrial participation in ischemic and traumatic neural cell death. "Journal of Neurotrauma", Volume 17, Issue 10, Pages 843–855. PMID 11063052.]

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.Ichas F and Mazat JP. 1998. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high- conductance state. "Biochimica et Biophysica Acta", Volume 1366, Issues 1–2, Pages 33–50. PMID 9714722. Accessed January 23, 2007. ] Schinder AF, Olson EC, Spitzer NC, and Montal M. 1996. [http://www.jneurosci.org/cgi/content/full/16/19/6125?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%22Mitochondrial+dysfunction+is+a+%09primary+event+in+glutamate+neurotoxicity%22&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT Mitochondrial dysfunction is a primary event in glutamate neurotoxicity.] "Journal of Neuroscience", Volume 16, Issue 19, Pages 6125-6133. PMID 8815895. Accessed January 23, 2007. ] White RJ and Reynolds IJ. 1996. [http://www.jneurosci.org/cgi/content/full/16/18/5688?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%22Mitochondrial+depolarization+in+glutamate-stimulated+neurons%3A+an+early+signal%22&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT Mitochondrial depolarization in glutamate-stimulated neurons: An early signal specific to excitotoxin exposure.] "Journal of Neuroscience", Volume 16, Number 18, Pages 5688–5697. PMID 8795624. ] MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.Honda HM and Ping P. 2006. Mitochondrial permeability transition in cardiac cell injury and death. "Cardiovascular Drugs and Therapy" Volume 20, Issue 6, Pages 425–432. PMID 17171295. ] 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, [Bopassa JC, Michel P, Gateau-Roesch O, Ovize M, Ferrera R. (2005). [http://ajpheart.physiology.org/cgi/content/full/288/6/H2750 Low-pressure reperfusion alters mitochondrial permeability transition] . "American Journal of Physiology, Heart and Circulation Physiology". Volume 288, Issue 6, Pages H2750–H2755. PMID 15653760. ] 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.Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, and Herman B. 1998. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. "Biochimica et Biophysica Acta". Volume 1366, Issues 1–2, Pages 177–196. PMID 9714796. ] MPT may also play a role in mitochondrial autophagy. Cells exposed to toxic amounts of Ca²⁺ ionophores also undergo MPT and death by necrosis.

MPTP Structure

The MPT pore is a nonselective, high conductance channel with multiple macromolecular components.Alano CC, Beutner G, Dirksen RT, Gross RA, and Sheu S-S. 2002. Mitochondrial permeability transition and calcium dynamics in striatal neurons upon intense NMDA receptor activation. "Journal of Neurochemistry", Volume 80, Issue 3, Pages 531-538. PMID 11905998. ] Haworth RA and Hunter DR. 1979. The Ca²⁺-induced membrane transition in mitochondria II. Nature of the Ca²⁺ trigger site. "Archives of Biochemistry and Biophysics", Volume 195, Issue 2, Pages 460-467. PMID 38751. ] It forms at sites where the inner and outer membranes of the mitochondria meet.Crompton M. 1999. [http://www.biochemj.org/bj/341/0233/bj3410233.htm The mitochondrial permeability transition pore and its role in cell death] . "Biochemical Journal". Volume 341, Pages 233-249. PMID 10393078. ] 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.Fiskum G. 2001. Mitochondrial dysfunction in the pathogenesis of acute neuronal cell death. Chapter 16 In "Mitochondria in pathogenesis". Lemasters JJ and Nieminen AL, eds. Kluwer Academic/Plenum Publishers. New York. Pages 317–331.] Cyclosporin A blocks the formation of the MPT pore by interacting with cyclophilin from the mitochondrial matrix and preventing its joining the pore.Sullivan PG, Thompson M, and Scheff SW. (2000). Continuous infusion of Cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. "Experimental Neurology". Volume 161, Issue 2, Pages 631-637. PMID 10686082. ] 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.Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, and Tsujimoto Y. (2005). Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. "Nature". Volume 434, Pages 652-658. PMID 15800626 ] However, the 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 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) [ Chinopoulos C, Starkov AA, Fiskum G. Cyclosporin A-insensitive permeability transition in brain mitochondria: Inhibition by 2-aminoethoxydiphenyl borate. J Biol Chem. 2003 Jul 25;278(30):27382-9. PMID 12750371 ] , 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.Brustovetsky N, Brustovetsky T, Jemmerson R, and Dubinsky JM. 2002. Calcium induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. "Journal of Neurochemistry", Volume 80, Issue 2, Pages 207-218. PMID 11902111.] Hunter DR and Haworth RA. 1979. The Ca2+-induced membrane transition in mitochondria I. The protective mechanisms. "Archives of Biochemistry and Biophysics", Volume 195, Issue 2, Pages 453-459. PMID 383019.] 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 between the inside and outside of mitochondrial membranes (known as permeability transition, or δψ).Armstrong JS, Yang H, Duan W, and Whiteman M. (2004). [http://www.jbc.org/cgi/content/full/279/48/50420 Cytochrome bc₁ regulates the mitochondrial permeability transition by two distinct pathways] . "Journal of Biological Chemistry". Volume 279 Issue 48, Pages 50420-50428. PMID 15364912. Accessed January 23, 2007. ] The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.Brustovetsky N, Brustovetsky T, Purl KJ, Capano M, Crompton M, and Dubinsky JM. 2003. [http://www.jneurosci.org/cgi/content/full/23/12/4858 Increased susceptibility of striatal mitochondria to calcium-induced permeability transition] . "The Journal of Neuroscience". Volume 23 Issue 12, Pages 4858-4867. PMID 12832508. Accessed January 23, 2007. ]

Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids,Garcia-Ruiz C, Colell A, Paris R, and Fernandez-Checa JC. 2000. Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. FASEB Journal, Volume 14, Issue 7, Pages 847-858.] and inorganic phosphate.Nicholls DG and Brand MD. 1980. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7406874 The nature of the calcium ion efflux induced in rat liver mitochondria by the oxidation of endogenous nicotinamide nucleotides.] "Biochemical Journal", Volume 188, Issue 1, 113-118.PMID 7406874. Full text article available. Accessed September 15, 2007.] However, these factors cannot open the pore without Ca²⁺, though at high enough concentrations, Ca²⁺ alone can induce MPT.Gunter TE, Gunter KK, Sheu SS, and Gavin CE. 1994. [Mitochondrial calcium transport: physiological and pathological relevance.] "American journal of Physiology", Volume 267, Issue 2, Pages C313-C339. PMID]

Stress in the endoplasmic reticulum can be a factor in triggering MPT. [Deniaud A, Sharaf El Dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C. 2007. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. "Oncogene", August 13, 2007, published online ahead of print. PMID 17700538. Accessed September 3, 2007.]

Things that cause the pore to close or remain closed include acidic conditions,Friberg H and Wieloch T. 2002. [Mitochondrial permeability transition in acute neurodegeneration.] "Biochimie", Volume 84, Issues 2-3, Pages 241-250.] high concentrations of ADP, high concentrations of ATP,Beutner G, Rück A, Riede B, Brdiczka D. 1998. Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. "Biochimica et Biophysica Acta", Volume 1368, Issue 1, Pages 7-18.] 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 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 excitotoxicity.Ichas F and Mazat JP. 1998. From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high- conductance state. "Biochimica et Biophysica Acta", Volume 1366, Issues 1-2, Pages 33-50. PMID 9714722. Retrieved on March 19, 2007.]

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 outer mitochondrial membrane uninhibited.Schinder AF, Olson EC, Spitzer NC, and Montal M. 1996. [http://www.jneurosci.org/cgi/content/full/16/19/6125 Mitochondrial dysfunction is a primary event in glutamate neurotoxicity.] "Journal of Neuroscience", Volume 16, Issue 19, Pages 6125-6133. PMID 8815895. Retrieved on March 19, 2007.] White RJ and Reynolds IJ. 1996. [http://www.jneurosci.org/cgi/content/full/16/18/5688 Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure.] "Journal of Neuroscience", Volume 16, Number 18, Pages 5688-5697. PMID 8795624. Retrieved on March 19, 2007.] 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.Stavrovskaya IG and Kristal BS. 2005. The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? "Free Radical Biology and Medicine". Volume 38, Issue 6, Pages 687-697. PMID 15721979. Accessed January 23, 2007. ] 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.Luetjens CM, Bui NT, Sengpiel B, Münstermann G, Poppe M, Krohn AJ, Bauerbach E, Krieglstein J, and Prehn JHM. 2000. [http://www.jneurosci.org/cgi/content/full/20/15/5715 Delayed mitochondrial dysfunction in excitotoxic neuron death: Cytochrome "c" release and a secondary increase in superoxide production.] "The Journal of Neuroscience", Volume 20, Issue 15, Pages 5715-5723. PMID 10908611. Accessed January 23, 2007.] 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.Büki A, Okonkwo DO, Wang KKW, and Povlishock JT. 2000. [http://www.jneurosci.org/cgi/content/full/20/8/2825?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%22Release+and+Caspase+Activation+%22&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT Cytochrome "c" release and caspase activation in traumatic axonal injury.] "Journal of Neuroscience". Volume 20, Issue 8, Pages 2825-2834. PMID 10751434. Accessed January 23, 2007. ] 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.Priault M, Chaudhuri B, Clow A, Camougrand N, Manon S. 1999. [http://content.febsjournal.org/cgi/content/full/260/3/684 Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement.] "European Journal of Biochemistry", Volume 260, Issue 3, Pages 684-691. PMID 10102996 Accessed January 23, 2007.]

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 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.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 molecules like Ca²⁺ to leave mitochondria quickly, in order to aid in the cycling of Ca²⁺ in healthy cells.Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC, and Brierley GP. 1992. Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. "American journal of physiology", Volume 262, Issue 6, Pages H1699-H1704.] Hunter DR and Haworth RA. 1979. The Ca²⁺-induced membrane transition in mitochondria. Transitional Ca²⁺ release. "Archives of Biochemistry and Biophysics", Volume 195, Issue 2, Pages 468-477.] If this is the case, MPT may be a harmful side effect of abnormal activity of a usually beneficial MPTP.

ee also

*NMDA receptor
*NMDA receptor antagonist
*Crista

References

External links

* [http://www.celldeath.de/encyclo/misc/pt.htm Mitochondrial Permeability Transition (PT)] from Celldeath.de. Accessed January 1, 2007.