Mitochondrial permeability transition pore

Roles in pathology

The MPTP was originally discovered by Haworth and Hunter{{Cite journal

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.{{Cite journal | doi-access = free

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.{{Cite journal | doi-access = free

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-D in the mitochondrial matrix.

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. Recent findings have identified ATAD3A, an inner mitochondrial membrane AAA+ ATPase, as a critical upstream modulator of mPTP formation, acting via regulation of mitochondrial cholesterol transport and cyclophilin D localization.

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.{{Cite journal | doi-access = free 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. The presence of free radicals, another result of excessive intracellular calcium concentrations, can also cause the MPT pore to open.{{Cite journal

Other factors that increase the likelihood that the MPTP will be induced include the presence of certain fatty acids,{{Cite journal | doi-access = free

Stress in the endoplasmic reticulum can be a factor in triggering MPT.{{Cite journal | doi-access = free

Conditions that cause the pore to close or remain closed include acidic conditions,{{Cite journal | doi-access = free

Effects

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

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. 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.{{Cite journal

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.{{Cite journal

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.{{Cite journal | doi-access = free

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.

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.{{Cite journal

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.{{Cite journal

References

References

1. (2025). "ATAD3A regulates the mitochondrial permeability transition pore and protects against ischemia-reperfusion injury".
2. (1993). "The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore". FEBS Letters.
3. (2007). "Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death". Nature Cell Biology.
4. (2004). "The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore". Nature.
5. (2012). "The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore". Mitochondrion.
6. (2010). "Regulation of the Inner Membrane Mitochondrial Permeability Transition by the Outer Membrane Translocator Protein (Peripheral Benzodiazepine Receptor)". Journal of Biological Chemistry.
7. (2005). "Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death". Nature.
8. (2005). "Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death". Nature.
9. (2025-06-17). "ATAD3A regulates mitochondrial permeability transition pore opening via cholesterol homeostasis".
10. (2010). "Complex Contribution of Cyclophilin D to Ca2+-induced Permeability Transition in Brain Mitochondria, with Relation to the Bioenergetic State". Journal of Biological Chemistry.
11. (2010). "The mitochondrial permeability transition from yeast to mammals". FEBS Letters.
12. (2007). "Selective degradation of mitochondria by mitophagy". Archives of Biochemistry and Biophysics.
13. 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.
14. (2002). "The oat mitochondrial permeability transition and its implication in victorin binding and induced cell death". The Plant Journal.
15. (1997). "Properties of a Cyclosporin-insensitive Permeability Transition Pore in Yeast Mitochondria". Journal of Biological Chemistry.
16. (2015). "Ca²⁺-dependent nonspecific permeability of the inner membrane of liver mitochondria in the guinea fowl (''Numida meleagris'')". Journal of Bioenergetics and Biomembranes.
17. (2007). "On the Opening of an Insensitive Cyclosporin a Non-specific Pore by Phenylarsine Plus Mersalyl". [[Cell Biochemistry and Biophysics]].