Mitochondrial permeability transition pore

The Mitochondrial Permeability Transition, or MPT, is defined as an increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Daltons 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.[1]

Roles in pathology

The MPTP was originally discovered by Haworth and Hunter[2] in 1979 and has been found to be involved in neurodegeneration, hepatotoxicity from Reye-related agents, cardiac necrosis and nervous and muscular dystrophies among other deleterious events inducing cell damage and death.[1][3][4][5]

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 receptors causes excessive calcium entry into the cell.[6][7][8] MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.[9] 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,[10] 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.[11] MPT may also play a role in mitochondrial autophagy.[11] Cells exposed to toxic amounts of Ca2+ ionophores also undergo MPT and death by necrosis.[11]

MPTP Structure

While the MPT modulation has been widely studied, little is known about its structure[12] . 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.[13][14] 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.[15][16] 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-D in the mitochondrial matrix.[17][18] 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.[19] However, these cells do die in response to stimuli that kill cells through apoptosis, suggesting that MPT does not control cell death by apoptosis.[19]

MPTP blockers

Agents that transiently 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),[20] bongkrekic acid and alisporivir (also known as Debio-025). TRO40303 is a newly synthetitised MPT blocker developed by Trophos company and currently is in Phase I clinical trial.[21]

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.[22][23] This is possibly because Ca2+ binds to and activates Ca2+ binding sites on the matrix side of the MPTP.[6] 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.[24] The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.[25]

Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids,[26] and inorganic phosphate.[27] However, these factors cannot open the pore without Ca2+, though at high enough concentrations, Ca2+ alone can induce MPT.[28]

Stress in the endoplasmic reticulum can be a factor in triggering MPT.[29]

Conditions that cause the pore to close or remain closed include acidic conditions,[30] high concentrations of ADP,[25][31] high concentrations of ATP,[32] 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.[24]

Effects of MPT

Multiple studies have found the MPT to be a key factor in the damage to neurons caused by excitotoxicity.[6][7][8]

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.[7][8] 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.[33] 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 ETC, such as cytochrome c, through the MPTP.[34] 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.[35] This event may lead mitochondria to swell and may cause the outer membrane to rupture, releasing cytochrome c.[35] 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.[36]

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.[9]

Possible evolutionary purpose of the MPTP

Despite the MPTP has been studied mainly in mitochondria from mammalian sources, mitochondria from diverse species also undergo a similar transition.[37] 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.[38] Under severe stress/pathologic conditions, MPTP opening would trigger injured cell death mainly through necrosis.[39]

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[6] 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.[31][40] 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,[41] yeasts, such as Saccharomyces cerevisiae,[42] birds, such as guinea fowl [43] and primitive vertebrates such as the Baltic lamprey.[44] 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[45] strongly suggesting this event may be a conserved characteristic throughout the eukaryotic domain.[46]

See also

References

  1. 1 2 Lemasters, J. J.; Theruvath, T. P.; Zhong, Z.; Nieminen, A. L. (2009). "Mitochondrial calcium and the permeability transition in cell death". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1787 (11): 1395–1401. doi:10.1016/j.bbabio.2009.06.009. PMC 2730424. PMID 19576166.
  2. ↑ Haworth, R. A.; Hunter, D. R. (1979). "The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site". Archives of Biochemistry and Biophysics 195 (2): 460–467. doi:10.1016/0003-9861(79)90372-2. PMID 38751.
  3. ↑ Fiskum, G. (2000). "Mitochondrial participation in ischemic and traumatic neural cell death". Journal of neurotrauma 17 (10): 843–855. doi:10.1089/neu.2000.17.843. PMID 11063052.
  4. ↑ Bernardi, P.; Bonaldo, P. (2008). "Dysfunction of Mitochondria and Sarcoplasmic Reticulum in the Pathogenesis of Collagen VI Muscular Dystrophies". Annals of the New York Academy of Sciences 1147: 303–311. doi:10.1196/annals.1427.009. PMID 19076452.
  5. ↑ Baines, C. P. (2010). "The Cardiac Mitochondrion: Nexus of Stress". Annual Review of Physiology 72: 61–80. doi:10.1146/annurev-physiol-021909-135929. PMID 20148667.
  6. 1 2 3 4 Ichas, F.; Mazat, J. P. (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 1366 (1–2): 33–50. doi:10.1016/S0005-2728(98)00119-4. PMID 9714722.
  7. 1 2 3 Schinder, A. F.; Olson, E. C.; Spitzer, N. C.; Montal, M. (1996). "Mitochondrial dysfunction is a primary event in glutamate neurotoxicity". The Journal of neuroscience : the official journal of the Society for Neuroscience 16 (19): 6125–6133. PMID 8815895.
  8. 1 2 3 White, R. J.; Reynolds, I. J. (1996). "Mitochondrial depolarization in glutamate-stimulated neurons: An early signal specific to excitotoxin exposure". The Journal of neuroscience : the official journal of the Society for Neuroscience 16 (18): 5688–5697. PMID 8795624.
  9. 1 2 Honda, H. M.; Ping, P. (2006). "Mitochondrial Permeability Transition in Cardiac Cell Injury and Death". Cardiovascular Drugs and Therapy 20 (6): 425–432. doi:10.1007/s10557-006-0642-0. PMID 17171295.
  10. ↑ Bopassa, J. C.; Michel, P.; Gateau-Roesch, O.; Ovize, M.; Ferrera, R. (2005). "Low-pressure reperfusion alters mitochondrial permeability transition". AJP: Heart and Circulatory Physiology 288 (6): H2750–H2755. doi:10.1152/ajpheart.01081.2004. PMID 15653760.
  11. 1 2 3 Lemasters, J. J.; Nieminen, A. L.; Qian, T.; Trost, L. C.; Elmore, S. P.; Nishimura, Y.; Crowe, R. A.; Cascio, W. E.; Bradham, C. A.; Brenner, D. A.; Herman, B. (1998). "The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy". Biochimica et Biophysica Acta 1366 (1–2): 177–196. doi:10.1016/S0005-2728(98)00112-1. PMID 9714796.
  12. ↑ Srinivasan, B. (2012). "Mitochondrial permeability transition pore: an enigmatic gatekeeper". New Horizons in Science & Technology (NHS&T) 1 (3): 47–51. ISSN 1929-2015.
  13. ↑ Szabó, I.; Zoratti, M. (1993). "The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore". FEBS Letters 330 (2): 201–205. doi:10.1016/0014-5793(93)80273-w. PMID 7689983.
  14. ↑ Baines, C. P.; Kaiser, R. A.; Sheiko, T.; Craigen, W. J.; Molkentin, J. D. (2007). "Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death". Nature Cell Biology 9 (5): 550–555. doi:10.1038/ncb1575. PMC 2680246. PMID 17417626.
  15. ↑ Kokoszka, J. E.; Waymire, K. G.; Levy, S. E.; Sligh, J. E.; Cai, J.; Jones, D. P.; MacGregor, G. R.; Wallace, D. C. (2004). "The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore". Nature 427 (6973): 461–465. doi:10.1038/nature02229. PMC 3049806. PMID 14749836.
  16. ↑ Varanyuwatana, P.; Halestrap, A. P. (2012). "The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore". Mitochondrion 12 (1): 120–125. doi:10.1016/j.mito.2011.04.006. PMC 3281194. PMID 21586347.
  17. ↑ Sileikyte, J.; Petronilli, V.; Zulian, A.; Dabbeni-Sala, F.; Tognon, G.; Nikolov, P.; Bernardi, P.; Ricchelli, F. (2010). "Regulation of the Inner Membrane Mitochondrial Permeability Transition by the Outer Membrane Translocator Protein (Peripheral Benzodiazepine Receptor)". Journal of Biological Chemistry 286 (2): 1046–1053. doi:10.1074/jbc.M110.172486. PMC 3020711. PMID 21062740.
  18. ↑ Baines, C. P.; Kaiser, R. A.; Purcell, N. H.; Blair, N. S.; Osinska, H.; Hambleton, M. A.; Brunskill, E. W.; Sayen, M. R.; Gottlieb, R. A.; Dorn, G. W.; Robbins, J.; Molkentin, J. D. (2005). "Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death". Nature 434 (7033): 658–662. doi:10.1038/nature03434. PMID 15800627.
  19. 1 2 Nakagawa, T.; Shimizu, S.; Watanabe, T.; Yamaguchi, O.; Otsu, K.; Yamagata, H.; Inohara, H.; Kubo, T.; Tsujimoto, Y. (2005). "Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death". Nature 434 (7033): 652–658. doi:10.1038/nature03317. PMID 15800626.
  20. ↑ Chinopoulos, C.; Starkov, A. A.; Fiskum, G. (2003). "Cyclosporin A-insensitive Permeability Transition in Brain Mitochondria: INHIBITION BY 2-AMINOETHOXYDIPHENYL BORATE". Journal of Biological Chemistry 278 (30): 27382–27389. doi:10.1074/jbc.M303808200. PMID 12750371.
  21. ↑ Le Lamer S (Feb 2014). "Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial.". J Transl Med. 12: 38. doi:10.1186/1479-5876-12-38. PMC 3923730. PMID 24507657.
  22. ↑ Brustovetsky, N.; Brustovetsky, T.; Jemmerson, R.; Dubinsky, J. M. (2002). "Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane". Journal of Neurochemistry 80 (2): 207–218. doi:10.1046/j.0022-3042.2001.00671.x. PMID 11902111.
  23. ↑ Hunter, D. R.; Haworth, R. A. (1979). "The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms". Archives of Biochemistry and Biophysics 195 (2): 453–459. doi:10.1016/0003-9861(79)90371-0. PMID 383019.
  24. 1 2 Doczi, J.; Turiák, L.; Vajda, S.; Mándi, M.; Töröcsik, B.; Gerencser, A. A.; Kiss, G.; Konràd, C.; Adam-Vizi, V.; Chinopoulos, C. (2010). "Complex Contribution of Cyclophilin D to Ca2+-induced Permeability Transition in Brain Mitochondria, with Relation to the Bioenergetic State". Journal of Biological Chemistry 286 (8): 6345–6353. doi:10.1074/jbc.M110.196600. PMC 3057831. PMID 21173147.
  25. 1 2 Brustovetsky, N.; Brustovetsky, T.; Purl, K. J.; Capano, M.; Crompton, M.; Dubinsky, J. M. (2003). "Increased susceptibility of striatal mitochondria to calcium-induced permeability transition". The Journal of neuroscience : the official journal of the Society for Neuroscience 23 (12): 4858–4867. PMID 12832508.
  26. ↑ García-Ruiz, C.; Colell, A.; París, R.; Fernández-Checa, J. C. (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 14 (7): 847–858. PMID 10783138.
  27. ↑ Nicholls, D. G.; Brand, M. D. (1980). "The nature of the calcium ion efflux induced in rat liver mitochondria by the oxidation of endogenous nicotinamide nucleotides". The Biochemical Journal 188 (1): 113–118. PMC 1162544. PMID 7406874.
  28. ↑ Gunter, T. E.; Gunter, K. K.; Sheu, S. S.; Gavin, C. E. (1994). "Mitochondrial calcium transport: Physiological and pathological relevance". The American journal of physiology 267 (2 Pt 1): C313–C339. PMID 8074170.
  29. ↑ 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 27 (3): 285–299. doi:10.1038/sj.onc.1210638. PMID 17700538.
  30. ↑ Friberg, H.; Wieloch, T. (2002). "Mitochondrial permeability transition in acute neurodegeneration". Biochimie 84 (2–3): 241–250. doi:10.1016/s0300-9084(02)01381-0. PMID 12022955.
  31. 1 2 Hunter, D. R.; Haworth, R. A. (1979). "The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release". Archives of Biochemistry and Biophysics 195 (2): 468–477. doi:10.1016/0003-9861(79)90373-4. PMID 112926.
  32. ↑ 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 1368 (1): 7–18. doi:10.1016/s0005-2736(97)00175-2. PMID 9459579.
  33. ↑ Stavrovskaya, I. G.; Kristal, B. S. (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 38 (6): 687–697. doi:10.1016/j.freeradbiomed.2004.11.032. PMID 15721979.
  34. ↑ Luetjens, C. M.; Bui, N. T.; Sengpiel, B.; Münstermann, G.; Poppe, M.; Krohn, A. J.; Bauerbach, E.; Krieglstein, J.; Prehn, J. H. (2000). "Delayed mitochondrial dysfunction in excitotoxic neuron death: Cytochrome c release and a secondary increase in superoxide production". The Journal of neuroscience : the official journal of the Society for Neuroscience 20 (15): 5715–5723. PMID 10908611.
  35. 1 2 Büki, A.; Okonkwo, D. O.; Wang, K. K.; Povlishock, J. T. (2000). "Cytochrome c release and caspase activation in traumatic axonal injury". The Journal of neuroscience : the official journal of the Society for Neuroscience 20 (8): 2825–2834. PMID 10751434.
  36. ↑ 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 / FEBS 260 (3): 684–691. doi:10.1046/j.1432-1327.1999.00198.x. PMID 10102996.
  37. ↑ Azzolin, L.; Von Stockum, S.; Basso, E.; Petronilli, V.; Forte, M. A.; Bernardi, P. (2010). "The mitochondrial permeability transition from yeast to mammals". FEBS Letters 584 (12): 2504–2509. doi:10.1016/j.febslet.2010.04.023. PMC 2878904. PMID 20398660.
  38. ↑ Kim, I.; Rodriguez-Enriquez, S.; Lemasters, J. J. (2007). "Selective degradation of mitochondria by mitophagy". Archives of Biochemistry and Biophysics 462 (2): 245–253. doi:10.1016/j.abb.2007.03.034. PMC 2756107. PMID 17475204.
  39. ↑ 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.
  40. ↑ Altschuld, R. A.; Hohl, C. M.; Castillo, L. C.; Garleb, A. A.; Starling, R. C.; Brierley, G. P. (1992). "Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes". The American journal of physiology 262 (6 Pt 2): H1699–H1704. PMID 1377876.
  41. ↑ Curtis, M. J.; Wolpert, T. J. (2002). "The oat mitochondrial permeability transition and its implication in victorin binding and induced cell death". The Plant Journal 29 (3): 295–312. doi:10.1046/j.0960-7412.2001.01213.x. PMID 11844107.
  42. ↑ Jung, D. W.; Bradshaw, P. C.; Pfeiffer, D. R. (1997). "Properties of a Cyclosporin-insensitive Permeability Transition Pore in Yeast Mitochondria". Journal of Biological Chemistry 272 (34): 21104–21112. doi:10.1074/jbc.272.34.21104. PMID 9261114.
  43. ↑ Vedernikov, A. A.; Dubinin, M. V.; Zabiakin, V. A.; Samartsev, V. N. (2015). "Ca2+-dependent nonspecific permeability of the inner membrane of liver mitochondria in the guinea fowl (Numida meleagris)". Journal of Bioenergetics and Biomembranes 47 (3): 235–242. doi:10.1007/s10863-015-9606-z. PMID 25690874.
  44. ↑ Savina, M. V.; Emelyanova, L. V.; Belyaeva, E. A. (2006). "Bioenergetic parameters of lamprey and frog liver mitochondria during metabolic depression and activity". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 145 (3–4): 296–305. doi:10.1016/j.cbpb.2006.07.011. PMID 17070716.
  45. ↑ García, N.; Martínez-Abundis, E.; Pavón, N.; Chávez, E. (2007). "On the Opening of an Insensitive Cyclosporin a Non-specific Pore by Phenylarsine Plus Mersalyl". Cell Biochemistry and Biophysics 49 (2): 84–90. doi:10.1007/s12013-007-0047-0. PMID 17906363.
  46. ↑ Uribe-Carvajal, S.; Luévano-Martínez, L. S. A.; Guerrero-Castillo, S.; Cabrera-Orefice, A.; Corona-De-La-Peña, N. A.; Gutiérrez-Aguilar, M. (2011). "Mitochondrial Unselective Channels throughout the eukaryotic domain". Mitochondrion 11 (3): 382–390. doi:10.1016/j.mito.2011.02.004. PMID 21385626.

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