ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration

Mnatsakanyan, Nelli; Jonas, Elizabeth A.

doi:10.1016/j.yjmcc.2020.05.013

Cited by 61 publications

(44 citation statements)

References 176 publications

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“…The various experimental evidences that have been offered for the involvement of the ATP synthase in forming the PTP/MMC [for reviews, see refs. 54,55] also support the present hypothesis. This is because these experiments relate to the entire F O F 1 -enzyme complex, and do not specifically address which subunits of the F O F 1 -ATP synthase are responsible for constituting the PTP/MMC.…”

Section: Experimental Evidence In Support Of the Hypothesis And Discusupporting

confidence: 90%

“…Current hypotheses of PTP/MMC composition and regulation have recently been reviewed [54,55]. These hypotheses can be classified as mechanisms involving mechanical force transmission.…”

Section: Activators and Inhibitors Of Ptp/ MMCmentioning

confidence: 99%

“…There are other salient differences between current hypotheses of the molecular composition of the PTP/ MMC and the hypothesis presented here, in addition to their classification above as mechanical-or electricalcentric respectively. Current models place the PTP/MMC at the dimer/tetramer interface of ATP synthase [54] or within the core of the c-ring [55]. However, the interface or the core possess a hydrophobic nature and are normally occupied by membrane lipids, which would need to be ejected out upon PTP/MMC activation in order to form an aqueous channel and allow the passage of ions.…”

Section: Experimental Evidence In Support Of the Hypothesis And Discumentioning

confidence: 99%

“…Several hypotheses of its molecular nature have been put forward, and several hypotheses have been rejected or contradicted by experimental work [51−55]. The molecular composition of the PTP/MMC is currently a subject of intense debate in the scientific literature [54,55]. A unifying molecular explanation for the complex regulation of the PTP/MMC has not been provided, and new ideas or hypotheses may be required.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

Nath

2020

Biomolecular Concepts

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The mitochondrial permeability transition (MPT) has been one of the longstanding enigmas in biology. Its cause is currently at the center of an extensive scientific debate, and several hypotheses on its molecular nature have been put forward. The present view holds that the transition arises from the opening of a high-conductance channel in the energy-transducing membrane, the permeability transition pore (PTP), also called the mitochondrial megachannel or the multiconductance channel (MMC). Here, the novel hypothesis is proposed that the aqueous access channels at the interface of the c-ring and the a-subunit of FO in the FOF1-ATP synthase are repurposed during induction of apoptosis and constitute the elusive PTP/ MMC. A unifying principle based on regulation by local potentials is advanced to rationalize the action of the myriad structurally and chemically diverse inducers and inhibitors of PTP/MMC. Experimental evidence in favor of the hypothesis and its differences from current models of PTP/MMC are summarized. The hypothesis explains in considerable detail how the binding of Ca2+ to a β-catalytic site (site 3) in the F1 portion of ATP synthase triggers the opening of the PTP/MMC. It is also shown to connect to longstanding proposals within Nath’s torsional mechanism of energy transduction and ATP synthesis as to how the binding of MgADP to site 3 does not induce PTP/MMC, but instead catalyzes physiological ATP synthesis in cell life. In the author’s knowledge, this is the first model that explains how Ca2+ transforms the FOF1-ATP synthase from an exquisite energy-conserving enzyme in cell life into an energy-dissipating structure that promotes cell death. This has major implications for basic as well as for clinical research, such as for the development of drugs that target the MPT, given the established role of PTP/MMC dysregulation in cancer, ischemia, cardiac hypertrophy, and various neurodegenerative diseases.

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Section: Experimental Evidence In Support Of the Hypothesis And Discusupporting

confidence: 90%

“…Current hypotheses of PTP/MMC composition and regulation have recently been reviewed [54,55]. These hypotheses can be classified as mechanisms involving mechanical force transmission.…”

Section: Activators and Inhibitors Of Ptp/ MMCmentioning

confidence: 99%

Section: Experimental Evidence In Support Of the Hypothesis And Discumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

Nath

2020

Biomolecular Concepts

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“…This ultimately leads to neuronal death. Although opening of the mitochondrial permeability transition pore (mtPTP), a large mitochondrial inner membrane death channel [ 4 , 5 , 6 ], occurs in both apoptotic and necrotic neurons, it may be regulated by Bcl-2 family proteins. Bcl-xL binds directly to the c-subunit of the F 1 Fo ATP synthase [ 7 ], a voltage-sensitive channel that acts like a mtPTP [ 8 , 9 ], preventing proton leak through the pore.…”

Section: Introductionmentioning

confidence: 99%

Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

et al. 2020

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Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approaches that block apoptotic pathways may prevent or delay neurodegenerative processes. Carotenoids are a group of pigments found in fruits, vegetables, and seaweeds that possess antioxidant properties. Over the last several decades, an increasing number of studies have demonstrated a protective role of carotenoids in neurodegenerative disease. In this review, we describe functions of commonly consumed carotenoids including lycopene, β-carotene, lutein, astaxanthin, and fucoxanthin and their roles in neurodegenerative disease models. We also discuss the underlying cellular mechanisms of carotenoid-mediated neuroprotection, including their antioxidant properties, role as signaling molecules, and as gene regulators that alleviate apoptosis-associated brain cell death.

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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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ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration

Cited by 61 publications

References 176 publications

A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

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

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ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration

Cited by 61 publications

References 176 publications

A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

A Novel Conceptual Model for the Dual Role of FOF1-ATP Synthase in Cell Life and Cell Death

Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

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

Contact Info

Product

Resources

About

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