Mitochondrial permeability transition

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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 permeability transition pore can form when mitochondria absorb too much calcium or in response to oxidative stress.^[1] Increasing membrane permeability causes mitochondria to become depolarized, meaning that the mitochondrial membrane potential, or difference in voltage between the inside and outside of their membranes (known as δψ), is lost. 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.

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] Additionally, it is thought to underlie the cell death induced by Reye's syndrome, since chemicals that can cause the syndrome, like salicylate and valproate, cause MPT.^[6] MPT may also play a role in mitochondrial autophagy.^[6]

Contents 1 MPTP Structure 2 MPT resulting from excessive Ca2+ 3 Effects of MPT 4 Possible evolutionary purpose of the MPTP 5 See also 6 References 7 External link

[edit] MPTP Structure

The MPT pore forms at sites where the inner and outer membranes meet.^[7] 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.^[8] Ciclosporin A blocks the formation of the MPT pore by interacting with cyclophilin from the mitochondrial matrix and preventing its joining the pore. ^[9]

[edit] MPT resulting from excessive Ca²⁺

High levels of Ca²⁺ within a cell can cause the MPT pore to open due to the dissipation of the difference in charge, called permeability transition, or δψ, across the inner membrane.^[10] The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.^[8]

[edit] Effects of MPT

In cell damage resulting from conditions such as neurodegenerative diseases and head injury, opening of the mitochondrial permeability transition pore can greatly reduce adenosine triphosphate production, and can cause ATP synthase to begin hydrolysing, rather than producing, ATP.^[11] 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 ETC components such as cytochrome c through the MPTP.^[12]

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.^[13] This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochrome c.^[13] 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.^[14]

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 and if it occurs to an even larger degree the cell is likely to undergo necrosis.^[5]

[edit] 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.^[15] There is controversy about the question of whether the MPTP is able to exist in a harmless, "low-conductance" state which would not induce MPT and which would allow certain molecules and ions to cross the mitochondrial membranes. If this is the case, MPT may be a harmful side effect of abnormal activity of a normally beneficial MPTP.

[edit] See also

• NMDA receptor
• NMDA receptor antagonist
• Crista

[edit] References

1. ^ Brustovetsky N, Brustovetsky T, Purl KJ, Capano M, Crompton M, and Dubinsky JM. 2003. 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.
2. ^ 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.
3. ^ Schinder AF, Olson EC, Spitzer NC, and Montal M. 1996. 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.
4. ^ White RJ and Reynolds IJ. 1996. 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. Accessed January 23, 2007.
5. ^ ^{a b} 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. Accessed January 23, 2007.
6. ^ ^{a b} 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. Accessed January 23, 2007.
7. ^ Crompton M. 1999. The mitochondrial permeability transition pore and its role in cell death. Biochemical Journal. Volume 341, Pages 233-249. PMID 10393078. Accessed January 23, 2007.
8. ^ ^{a b} 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.
9. ^ 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. Accessed January 23, 2007.
10. ^ Armstrong JS, Yang H, Duan W, and Whiteman M. (2004). 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.
11. ^ 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.
12. ^ Luetjens CM, Bui NT, Sengpiel B, Münstermann G, Poppe M, Krohn AJ, Bauerbach E, Krieglstein J, and Prehn JHM. 2000. 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.
13. ^ ^{a b} Büki A, Okonkwo DO, Wang KKW, and Povlishock JT. 2000. 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.
14. ^ Priault M, Chaudhuri B, Clow A, Camougrand N, Manon S. 1999. 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.
15. ^ 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.

[edit] External link

• Mitochondrial Permeability Transition (PT) from Celldeath.de. Accessed January 1, 2007.