The unique histidine in OSCP subunit of F‐ATP synthase mediates inhibition of the permeability transition pore by acidic pH

Antoniel, Manuela; Jones, Kristen L.; Antonucci, Salvatore; Spolaore, Barbara; Fogolari, Federico; Petronilli, Valeria; Giorgio, Valentina; Carraro, Michela; Lisa, Fabio Di; Forte, Michael; Szabó, Ildikò; Lippe, Giovanna; Bernardi, Paolo

doi:10.15252/embr.201744705

Cited by 97 publications

(98 citation statements)

References 73 publications

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“…The molecular identification of the PTP allowed a better understanding of the interplay between the inducers of PT and the pore itself. For example, the reversible protonation of a histidine residue, located in the oligomycin sensitivity-conferring protein (OSCP) unit of the ATP synthase, has been shown to inhibit the opening of the pore (Antoniel et al 2018). The Ca 2+ -binding site of ATP synthase, which allows the opening of the pore, has recently been identified.…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Wacquier

Combettes

Dupont

2019

Cold Spring Harb Perspect Biol

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Intracellular Ca 2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca 2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca 2+ transporters also allow for Ca 2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca 2+ stimulate the production of ATP, which allows the cells to cope with the increased energy demand created by the stimulus. Less widely appreciated is the fact that Ca 2+ handling by mitochondria also shapes cytosolic Ca 2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca 2+ increases can be altered by modifying the rates of Ca 2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca 2+ signaling, highlighting not only the consequences of cytosolic Ca 2+ changes on mitochondrial Ca 2+ , but also how cytosolic Ca 2+ dynamics is controlled by modifications of the Ca 2+ -handling properties and the metabolism of mitochondria.

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Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Wacquier

Combettes

Dupont

2019

Cold Spring Harb Perspect Biol

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“…This site appears to coincide with the catalytic core of F-ATP synthase, which coordinates Mg 2+ and adenine nucleotides and discriminates between Me 2+ through a conserved Thr residue on subunit b [14]. The most potent inhibitors of the PTP are matrix H + , with channel block at pH 6.5, and this effect depends on protonation of the unique His residue of OSCP subunit [15]. The involvement of F-ATP synthase in PTP formation is also supported by the effect of some specific enzyme interactors on the electrophysiological activity of the pore.…”

Section: +mentioning

confidence: 99%

“…and Mg 2+ at the catalytic site [51], confers resistance to Ca 2+ -induced PTP opening and cell death [14]; (iii) H112Q and H112Y mutations of OSCP subunit made the PTP/MMC totally refractory to inhibition by H + , the most effective PTP blockers [15]; and (iv) an R107A mutation of yeast subunit g completely blunted the effects of phenylglyoxal on the permeability transition [52]. On the other hand, genetic ablation of either the OSCP or b subunits [46] or of subunit c [53] led to the assembly of defective F-ATP synthase.…”

Section: +mentioning

confidence: 99%

High-Conductance Channel Formation in Yeast Mitochondria is Mediated by F-ATP Synthase e and g Subunits

Carraro

Checchetto

Sartori

et al. 2018

Cell Physiol Biochem

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Background/Aims: The permeability transition pore (PTP) is an unselective, Ca²⁺-dependent high conductance channel of the inner mitochondrial membrane whose molecular identity has long remained a mystery. The most recent hypothesis is that pore formation involves the F-ATP synthase, which consistently generates Ca²⁺-activated channels. Available structures do not display obvious features that can accommodate a channel; thus, how the pore can form and whether its activity can be entirely assigned to F-ATP synthase is the matter of debate. In this study, we investigated the role of F-ATP synthase subunits e, g and b in PTP formation. Methods: Yeast null mutants for e, g and the first transmembrane (TM) α-helix of subunit b were generated and evaluated for mitochondrial morphology (electron microscopy), membrane potential (Rhodamine123 fluorescence) and respiration (Clark electrode). Homoplasmic C23S mutant of subunit a was generated by in vitro mutagenesis followed by biolistic transformation. F-ATP synthase assembly was evaluated by BN-PAGE analysis. Cu²⁺ treatment was used to induce the formation of F-ATP synthase dimers in the absence of e and g subunits. The electrophysiological properties of F-ATP synthase were assessed in planar lipid bilayers. Results: Null mutants for the subunits e and g display dimer formation upon Cu²⁺ treatment and show PTP-dependent mitochondrial Ca²⁺ release but not swelling. Cu²⁺ treatment causes formation of disulfide bridges between Cys23 of subunits a that stabilize dimers in absence of e and g subunits and favors the open state of wild-type F-ATP synthase channels. Absence of e and g subunits decreases conductance of the F-ATP synthase channel about tenfold. Ablation of the first TM of subunit b, which creates a distinct lateral domain with e and g, further affected channel activity. Conclusion: F-ATP synthase e, g and b subunits create a domain within the membrane that is critical for the generation of the high-conductance channel, thus is a prime candidate for PTP formation. Subunits e and g are only present in eukaryotes and may have evolved to confer this novel function to F-ATP synthase.

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“…OSCP also undergoes regulatory posttranslational modifications. The possible presence of flexible regions in OSCP is intriguing, because such regions could influence the position of the peripheral stalk and thus potentially modulate the membrane‐embedded Fo sector where, as we will discuss more in detail in the following paragraphs, the permeability transition pore (PTP) may form (Antoniel et al, ; Giorgio et al, ).…”

Section: Structure Interactions and Assembly Of The Oscp Subunitmentioning

confidence: 99%

OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore

Giorgio¹,

Fogolari

Lippe

et al. 2018

British J Pharmacology

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The permeability transition pore (PTP) is a latent, high‐conductance channel of the inner mitochondrial membrane. When activated, it plays a key role in cell death and therefore in several diseases. The investigation of the PTP took an unexpected turn after the discovery that cyclophilin D (the target of the PTP inhibitory effect of cyclosporin A) binds to FOF1 (F)‐ATP synthase, thus inhibiting its catalytic activity by about 30%. This observation was followed by the demonstration that binding occurs at a particular subunit of the enzyme, the oligomycin sensitivity conferral protein (OSCP), and that F‐ATP synthase can form Ca2+‐activated, high‐conductance channels with features matching those of the PTP, suggesting that the latter originates from a conformational change in F‐ATP synthase. This review is specifically focused on the OSCP subunit of F‐ATP synthase, whose unique features make it a potential pharmacological target both for modulation of F‐ATP synthase and its transition to a pore. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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The unique histidine in OSCP subunit of F‐ATP synthase mediates inhibition of the permeability transition pore by acidic pH

Cited by 97 publications

References 73 publications

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

High-Conductance Channel Formation in Yeast Mitochondria is Mediated by F-ATP Synthase e and g Subunits

OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore

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