Inorganic polyphosphate (polyP) as an activator and structural component of the mitochondrial permeability transition pore

Solesio, María E.; Elustondo, Pia A.; Zakharian, Eleonora; Pavlov, Evgeny

doi:10.1042/bst20150206

Cited by 42 publications

(41 citation statements)

References 91 publications

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“…More detailed discussion of this model in comparison with other current views can be found in Solesio et al . 33 Finally, patch-clamp studies indicate that very few mPTP channels are present in the mitochondria. 34,35 However, mitochondria contain high amounts of C-subunit oligomers, which is inconsistent with the relatively rare detection of mPTP.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Elustondo

Nichols

Negoda

et al. 2016

Cell Death Discovery

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Mitochondrial permeability transition pore (mPTP) opening allows free movement of ions and small molecules leading to mitochondrial membrane depolarization and ATP depletion that triggers cell death. A multi-protein complex of the mitochondrial ATP synthase has an essential role in mPTP. However, the molecular identity of the central 'pore' part of mPTP complex is not known. A highly purified fraction of mammalian mitochondria containing C-subunit of ATPase (C-subunit), calcium, inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB) forms ion channels with properties that resemble the native mPTP. We demonstrate here that amount of this channel-forming complex dramatically increases in intact mitochondria during mPTP activation. This increase is inhibited by both Cyclosporine A, an inhibitor of mPTP and Ruthenium Red, an inhibitor of the Mitochondrial Calcium Uniporter. Similar increases in the amount of complex formation occurs in areas of mouse brain damaged by ischemia-reperfusion injury. These findings suggest that calcium-induced mPTP is associated with de novo assembly of a channel comprising C-subunit, polyP and PHB.

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Section: Discussionmentioning

confidence: 99%

“…More detailed discussion of this model in comparison with other current views can be found in Solesio et al . 33 …”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Elustondo

Nichols

Negoda

et al. 2016

Cell Death Discovery

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“…The mPTP has also been proposed to arise from PolyP interaction and association with the proteinaceous components whereby the PolyP provides Ca 2+ and voltage sensitivity and selectivity of the pore as reviewed by (Solesio et al 2016b). According to available evidence, the mPTP complex must account for the known biophysical and structural properties and, at a minimum, contain a matrix side divalent cation binding site that is inhibitory when bound to Mg 2+ and activating when bound to Ca 2+ (where the site favors Ca 2+ binding through CypD isomerase activity on the pore).…”

Section: Models Of the Mptpmentioning

confidence: 99%

Mitochondrial Ca2+ and regulation of the permeability transition pore

Hurst

Hoek

Sheu

2016

J Bioenerg Biomembr

169

142

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The mitochondrial permeability transition pore was originally described in the 1970’s as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore’s open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

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“…PolyP also influences the mitochondrial ion transport system via modulation of the mitochondrial permeability transition pore (mPTP). [18][19][20][21] It is therefore clear that polyP plays a key role in cell death and in controlling mitochondrial metabolism. 22,23 Radiation therapy is a powerful approach to eliminate tumor tissue.…”

Section: Introductionmentioning

confidence: 99%

Inorganic polyphosphate enhances radio-sensitivity in a human non–small cell lung cancer cell line, H1299

et al. 2017

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Inorganic polyphosphate is a linear polymer containing tens to hundreds of orthophosphate residues linked by highenergy phosphoanhydride bonds. Polyphosphate has been recognized as a potent anti-metastasis reagent. However, the molecular mechanism underlying polyphosphate action on cancer cells is poorly understood. In this study, we investigated the involvement of polyphosphate in radio-sensitivity using a human non-small cell lung cancer cell line, H1299. We found that polyphosphate treatment decreases cellular adenosine triphosphate levels, suggesting a disruption of energy metabolism. We also found that the induction of DNA double-strand breaks was enhanced in polyphosphatetreated cells after X-ray irradiation and colony formation assay revealed that cell survival decreased compared with that of the control groups. These findings suggest that polyphosphate is a promising radio-sensitizer for cancer cells. Therefore, we hypothesized that polyphosphate treatment disrupts adenosine triphosphate-mediated energy transfer for cellular survival and DNA repair, thereby reducing the cellular capability to resist X-ray irradiation.

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Inorganic polyphosphate (polyP) as an activator and structural component of the mitochondrial permeability transition pore

Cited by 42 publications

References 91 publications

Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Mitochondrial Ca2+ and regulation of the permeability transition pore

Inorganic polyphosphate enhances radio-sensitivity in a human non–small cell lung cancer cell line, H1299

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