The mitochondrial permeability transition pore in cell death: A promising drug binding bioarchitecture

Nesci, Salvatore

doi:10.1002/med.21635

Cited by 41 publications

(33 citation statements)

References 19 publications

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“…Future studies, aiming at enlightening the supramolecular F 1 F O -ATPase organization, are expected to add further details to shed light on the structural changes in the enzyme complex and on its relationship with the mPTP. On these bases, the multi-tasking F 1 F O -ATPase may emerge as a promising drug binding bioarchitecture to counteract mPTP-related diseases [38].…”

Section: Resultsmentioning

confidence: 99%

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Algieri

Trombetti

Pagliarani

et al. 2020

Archives of Biochemistry and Biophysics

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Phenylglyoxal (PGO), known to cause post-translational modifications of Arg residues, was used to highlight the role of arginine residues of the F 1 F O-ATPase, which may be crucial to yield for the mitochondrial permeability transition pore (mPTP). In swine heart mitochondria PGO inhibits ATP hydrolysis by the F 1 F O-ATPase either sustained by the natural cofactor Mg 2+ or by Ca 2+ by a similar uncompetitive inhibition mechanism, namely the tertiary complex (ESI) only forms when the ATP substrate is already bound to the enzyme, and with similar strength, as shown by the similar K'i values (0.82±0.07 mM in presence of Mg 2+ and 0.64±0.05 mM in the presence of Ca 2+). Multiple inhibitor analysis indicates that features of the F 1 catalytic sites and/or the F O proton binding sites are apparently unaffected by PGO. However, PGO and F 1 or F O inhibitors can bind the enzyme combine simultaneously. However they mutually hinder to bind the Mg 2+-activated F 1 F O-ATPase, whereas they do not mutually exclude to bind for the Ca 2+-activated F 1 F O-ATPase. The putative formation of PGO-arginine adducts, and the consequent spatial rearrangement in the enzyme structure, inhibits the F 1 F O-ATPase activity but, as shown by the calcium retention capacity evaluation in intact mitochondria, apparently favours the mPTP formation.

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Section: Resultsmentioning

confidence: 99%

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Algieri

Trombetti

Pagliarani

et al. 2020

Archives of Biochemistry and Biophysics

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“…The F 1 domain which hydrolyzes ATP in the presence of Ca 2+ drives the mechanical‐power transmission which results in F O conductance to H + . Consistently, the poor H + ‐pumping activity of the Ca 2+ ‐dependent F 1 F O ‐ATP(hydrol)ase fails to energize the IMM, mainly because the same enzyme activity is a key PTP constituent, and most likely the PTP opening prevents and masks Δ p formation 33,36 …”

Section: Resultsmentioning

confidence: 98%

Ca²⁺ as cofactor of the mitochondrial H⁺‐translocating F₁F_O‐ATP(hydrol)ase

Nesci

Pagliarani

2021

Proteins

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The mitochondrial F1FO‐ATPase in the presence of the natural cofactor Mg2+ acts as the enzyme of life by synthesizing ATP, but it can also hydrolyze ATP to pump H+. Interestingly, Mg2+ can be replaced by Ca2+, but only to sustain ATP hydrolysis and not ATP synthesis. When Ca2+ inserts in F1, the torque generation built by the chemomechanical coupling between F1 and the rotating central stalk was reported as unable to drive the transmembrane H+ flux within FO. However, the failed H+ translocation is not consistent with the oligomycin‐sensitivity of the Ca2+‐dependent F1FO‐ATP(hydrol)ase. New enzyme roles in mitochondrial energy transduction are suggested by recent advances. Accordingly, the structural F1FO‐ATPase distortion driven by ATP hydrolysis sustained by Ca2+ is consistent with the permeability transition pore signal propagation pathway. The Ca2+‐activated F1FO‐ATPase, by forming the pore, may contribute to dissipate the transmembrane H+ gradient created by the same enzyme complex.

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“…The pore's molecular composition and architecture are being studied in some leading laboratories; however, they remain unknown. Non-specific transition is supposed to be provided by a multi-protein complex, which is composed of an anion channel in an outer mitochondrial membrane (VDAC), ANT, and cyclophilin D (CyPD), as well as hexokinase and proteins Bcl-2 [18,19].…”

Section: Introductionmentioning

confidence: 99%

The Regulation of Non-Specific Membrane Permeability Transition in Yeast Mitochondria under Oxidative Stress

Исакова

Klein

Deryabina

2021

Microbiology Research

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In this study, the mechanism of non-specific membrane permeability (yPTP) in the Endomyces magnusii yeast mitochondria under oxidative stress due to blocking the key antioxidant enzymes has been investigated. We used monitoring the membrane potential at the cellular (potential-dependent staining) and mitochondrial levels and mitochondria ultra-structural images with transmission electron microscopy (TEM) to demonstrate the mitochondrial permeability transition induction due to the pore opening. Analysis of the yPTP opening upon respiring different substrates showed that NAD(P)H completely blocked the development of the yPTP. The yPTP opening was inhibited by 5–20 mM Pi, 5 mM Mg2+, adenine nucleotides (AN), 5 mM GSH, the inhibitor of the Pi transporter (PiC), 100 μM mersalyl, the blockers of the adenine nucleotide transporter (ANT) carboxyatractyloside (CATR), and bongkrekic acid (BA). We concluded that the non-specific membrane permeability pore opens in the E. magnusii mitochondria under oxidative stress, and the ANT and PiC are involved in its formation. The crucial role of the Ca2+ ions in the process has not been confirmed. We showed that the Ca2+ ions affected the yPTP both with and without the Ca2+ ionophore ETH129 application insignificantly. This phenomenon in the E. magnusii yeast unites both mitochondrial unselective channel (ScMUC) features in the Saccharomyces cerevisiae mitochondria and the classical membrane pore in the mammalian ones (mPTP).

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The mitochondrial permeability transition pore in cell death: A promising drug binding bioarchitecture

Cited by 41 publications

References 19 publications

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Ca²⁺ as cofactor of the mitochondrial H⁺‐translocating F₁F_O‐ATP(hydrol)ase

The Regulation of Non-Specific Membrane Permeability Transition in Yeast Mitochondria under Oxidative Stress

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The mitochondrial permeability transition pore in cell death: A promising drug binding bioarchitecture

Cited by 41 publications

References 19 publications

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Phenylglyoxal inhibition of the mitochondrial F1FO-ATPase activated by Mg2+ or by Ca2+ provides clues on the mitochondrial permeability transition pore

Ca2+ as cofactor of the mitochondrial H+‐translocating F1FO‐ATP(hydrol)ase

The Regulation of Non-Specific Membrane Permeability Transition in Yeast Mitochondria under Oxidative Stress

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Ca²⁺ as cofactor of the mitochondrial H⁺‐translocating F₁F_O‐ATP(hydrol)ase