Calcium and regulation of the mitochondrial permeability transition

Giorgio, Valentina; Guo, Lishu; Bassot, Claudio; Petronilli, Valeria; Bernardi, Paolo

doi:10.1016/j.ceca.2017.05.004

Cited by 155 publications

(130 citation statements)

References 123 publications

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“…For instance, among PTP inducers, Bz423 binds specifically the OSCP subunit of the enzyme [16] and consistently activates channel activity, whereas ADP/Mg 2+ and AMP-PNP, which bind the catalytic domain, inhibit channel opening [2]. Our working hypothesis is that the PTP forms from F-ATP synthase dimers (or higher order structures); and that a Ca 2+ -induced conformational change originating from the catalytic site is transmitted through OSCP and the peripheral stalk to the dimerization subunits e and g causing PTP opening within the inner membrane [17]. Consistently, genetic ablation of yeast subunits e and g causes desensitization of the pore to Ca 2+ with increased resistance to opening [4,18], yet whether these subunits directly contribute to channel formation remains unknown.…”

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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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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“…Jonas and Coworkers also observed high-conductance channel activity that could be assigned to the F-ATP synthase and was matched by reconstitution with purified c subunit [64]. These Authors suggested that pore formation occurs within the c ring following Ca 2+ -dependent displacement of the c, d and e subunits [64], whereas our laboratory proposed that the channel forms at the interface between adjacent monomers in the dimers [60,80]. Irrespective of the mechanism, however, these results are consistent with the possible generation of channels from F-ATP synthase.…”

Section: Reconstitution Of Channel Activity With F-atp Synthase Prepamentioning

confidence: 81%

F‐ATP synthase and the permeability transition pore: fewer doubts, more certainties

et al. 2019

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Whether the mitochondrial permeability transition pore (PTP), also called mitochondrial megachannel (MMC), originates from the F‐ATP synthase is a matter of controversy. This hypothesis is supported both by site‐directed mutagenesis of specific residues of F‐ATP synthase affecting regulation of the PTP/MMC and by deletion of specific subunits causing dramatic changes in channel conductance. In contrast, human cells lacking an assembled F‐ATP synthase apparently display persistence of the PTP. We discuss recent data that shed new light on this controversy, supporting the conclusion that the PTP/MMC originates from a Ca2+‐dependent conformational change in F‐ATP synthase allowing its reversible transformation into a high‐conductance channel.

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“…Alteration in mitochondrial membrane potential can affect, among other processes, the opening of mitochondrial permeability transition pore. This event can also be triggered by calcium dyshomeostasis [10,11], a process in which NCLX, the mitochondrial calcium exchanger, plays a relevant role [12,13].…”

Section: Introductionmentioning

confidence: 99%

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

Britti¹,

Delaspre²,

Medina-Carbonero³

et al. 2020

Preprint

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Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential. Accordingly, apoptotic markers and neurite degeneration are reduced resulting in cell survival recovery with calcitriol supplementation. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes;remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

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Calcium and regulation of the mitochondrial permeability transition

Cited by 155 publications

References 123 publications

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

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

F‐ATP synthase and the permeability transition pore: fewer doubts, more certainties

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

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