Mitochondrial permeability transition pore

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The mitochondrial permeability transition pore, or 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. Mitochondrial permeability transition, an increase in the permeability of the mitochondrial membrane to molecules weighing less than 1500 Daltons, results from opening the permeability transition pore. Induction of the pore can lead to mitochondrial swelling and cell death.

The permeability transition pore can form when mitochondria absorb too much calcium or in response to oxidative stress (Brustovetsky et al., 2003). 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.

Opening of the MPT pore is one of the major causes of cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium to enter the cell.

Contents

[edit] Structure

The MPT pore forms at sites where the inner and outer membranes meet (Crompton, 1999). Several proteins 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, 2001). Ciclosporin (cyclosporine A) blocks the formation of the MPT pore by interacting with cyclophilin from the mitochondrial matrix and preventing its joining the pore (Sullivan et al., 2000).

[edit] Opening 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 (Armstrong, 2004). The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open (Fiskum, 2001).

[edit] Effects of pore opening

In cell damage resulting from conditions such as neurodegenerative diseases and head injury, opening of the mitochondrial permeability transition pore can cause adenosine triphosphate production to stop, and can cause ATP synthase to begin hydrolysing, rather than producing, ATP (Stavrovskaya and Kristal, 2005). 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 to rid the cell of excess calcium.

Opening the MPT pore 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 are also produced as a result of opening the MPT pore.

Opening of the MPT pore causes mitochondria to become permeable to molecules smaller than 1.5 kDa, which, once inside, draw water in through osmosis (as reviewed in Büki et al., 2000). This event leads mitochondria to swell and the outer membrane to rupture, releasing cytochrome c (Büki et al., 2000). Cytochrome-c can in turn cause the cell to go through apoptosis ("commit suicide") by activating pro-apoptotic factors.

[edit] Possible evolutionary purpose

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 and Hunter, 2001).

[edit] See also

[edit] References

  • Armstrong J. S., 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.
  • 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.
  • 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.
  • Crompton M. 1999. The mitochondrial permeability transition pore and its role in cell death. Biochemical Journal. Volume 341, Pages 233-249.
  • 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.
  • 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.
  • 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.
  • 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.

[edit] External link

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