Potential role of subunit c of F0F1-ATPase and subunit c of storage body in the mitochondrial permeability transition. Effect of the phosphorylation status of subunit c on pore opening

Azarashvili, Tamara; Odinokova, Irina; Bakunts, Anush; Ternovsky, Vadim I.; Krestinina, Olga; Tyynelä, Jaana; Saris, Nils‐Erik L.

doi:10.1016/j.ceca.2013.12.002

Cited by 100 publications

(91 citation statements)

References 61 publications

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“…Another conserved Ca 2+ binding site has been described in the N-terminus of F O subunit c, 156,157 which could also represent a candidate for PTP inhibition by Ca 2+ in the intermembrane space. Ca 2+ binding to subunit c purified from neuronal plasma membrane and reconstituted in artificial membranes was able to block monovalent cation currents 157 , and Ca 2+ binding to subunit c inhibited H + translocation in bacteria and chloroplasts, 158 suggesting that Ca 2+ could alter the c ring conformation.…”

Section: F-atp Synthase and Ptp Formation In The Heartmentioning

confidence: 99%

From ATP to PTP and Back

Bernardi

Lisa

Fogolari

et al. 2015

Circulation Research

102

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Mitochondria play a fundamental role in heart physiology, but are also key effectors of dysfunction and death. This dual role assumes a new meaning following recent advances on the nature and regulation of the permeability transition pore, an inner membrane channel whose opening requires matrix Ca2+ and is modulated by many effectors including reactive oxygen species, matrix cyclophilin D, Pi and matrix pH. The recent demonstration that the F-ATP synthase can reversibly undergo a Ca2+-dependent transition to form a channel that mediates the permeability transition opens new perspectives to the field. These findings demand a reassessment of the modifications of F-ATP synthase that take place in the heart under pathological conditions and of their potential role in determining the transition of F-ATP synthase from and energy-conserving into an energy-dissipating device.

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Section: F-atp Synthase and Ptp Formation In The Heartmentioning

confidence: 99%

From ATP to PTP and Back

Bernardi

Lisa

Fogolari

et al. 2015

Circulation Research

102

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“…This idea is attractive because isolated purified ATP synthasomes (or SMVs) contain all the inner membrane PT regulatory components including the phosphate carrier, ANT and CypD as well as most of the proteins found within the ATP synthase complex (Ko et al, 2003; Chen et al, 2004). In addition, subunit c was found to participate in mPTP function within the complex composed of the ATP synthase, ANT, and PiC (Azarashvili et al, 2014). The authors of this report hypothesized that dephosphorylation of subunit c occurs in the presence of high matrix calcium, leading to opening of mPTP and mitochondrial swelling in a CsA-sensitive fashion.…”

Section: Permeability Transition Is the Great Uncouplermentioning

confidence: 99%

Bcl-xL in neuroprotection and plasticity

2014

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Accepted features of neurodegenerative disease include mitochondrial and protein folding dysfunction and activation of pro-death factors. Neurons that experience high metabolic demand or those found in organisms with genetic mutations in proteins that control cell stress may be more susceptible to aging and neurodegenerative disease. In neurons, events that normally promote growth, synapse formation, and plasticity are also often deployed to control neurotoxicity. Such protective strategies are coordinated by master stress-fighting proteins. One such specialized protein is the anti-cell death Bcl-2 family member Bcl-xL, whose myriad death-protecting functions include enhancement of bioenergetic efficiency, prevention of mitochondrial permeability transition channel activity, protection from mitochondrial outer membrane permeabilization (MOMP) to pro-apoptotic factors, and improvement in the rate of vesicular trafficking. Synapse formation and normal neuronal activity provide protection from neuronal death. Therefore, Bcl-xL brings about synapse formation as a neuroprotective strategy. In this review we will consider how this multi-functional master regulator protein uses many strategies to enhance synaptic and neuronal function and thus counteracts neurodegenerative stimuli.

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“…If the PTP is associated with the ATP synthase complex, it is likely that it will involve one or more of the membrane subunits, and one proposal that has been made is that the c 8 -ring of the human ATP synthase provides the mitochondrial PTP (33)(34)(35). To test this proposal, as described here, we have disrupted ATP5G1, ATP5G2, and ATP5G3 together in a single clone of a near-haploid human cell line and investigated whether the PTP, which is present in the parent HAP1 cells, persists in the mutant cells devoid of subunit c.…”

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confidence: 99%

Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase

Ford

Carroll

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

217

241

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The permeability transition in human mitochondria refers to the opening of a nonspecific channel, known as the permeability transition pore (PTP), in the inner membrane. Opening can be triggered by calcium ions, leading to swelling of the organelle, disruption of the inner membrane, and ATP synthesis, followed by cell death. Recent proposals suggest that the pore is associated with the ATP synthase complex and specifically with the ring of c-subunits that constitute the membrane domain of the enzyme's rotor. The c-subunit is produced from three nuclear genes, ATP5G1, ATP5G2, and ATP5G3, encoding identical copies of the mature protein with different mitochondrial-targeting sequences that are removed during their import into the organelle. To investigate the involvement of the c-subunit in the PTP, we generated a clonal cell, HAP1-A12, from near-haploid human cells, in which ATP5G1, ATP5G2, and ATP5G3 were disrupted. The HAP1-A12 cells are incapable of producing the c-subunit, but they preserve the characteristic properties of the PTP. Therefore, the c-subunit does not provide the PTP. The mitochondria in HAP1-A12 cells assemble a vestigial ATP synthase, with intact F 1 -catalytic and peripheral stalk domains and the supernumerary subunits e, f, and g, but lacking membrane subunits ATP6 and ATP8. The same vestigial complex plus associated c-subunits was characterized from human 143B ρ 0 cells, which cannot make the subunits ATP6 and ATP8, but retain the PTP. Therefore, none of the membrane subunits of the ATP synthase that are involved directly in transmembrane proton translocation is involved in forming the PTP.human mitochondria | ATP synthase | permeability transition pore | subunit c | ATP5G

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Potential role of subunit c of F0F1-ATPase and subunit c of storage body in the mitochondrial permeability transition. Effect of the phosphorylation status of subunit c on pore opening

Cited by 100 publications

References 61 publications

From ATP to PTP and Back

From ATP to PTP and Back

Bcl-xL in neuroprotection and plasticity

Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase

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