A mitochondrial megachannel resides in monomeric F1FO ATP synthase

Mnatsakanyan, Nelli; Llaguno, Marc C.; Yang, Youshan; Yan, Yangyang; Weber, Joachim; Sigworth, Fred J.; Jonas, Elizabeth A.

doi:10.1038/s41467-019-13766-2

Cited by 119 publications

(125 citation statements)

References 63 publications

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“…In two independent studies, highly purified ATP synthase complexes were recently confirmed to possess channel activity consistent with the biophysical characteristics of the mPTP, strongly supporting the identification of the ATP synthase as the sole component of the mPTP pore [130,131]. Further, monomeric complexes were sufficient to mediate mPTP-like channel activity [131], thus distinguishing the channel functions of ATP synthase monomers from the role of ATP synthase dimers in mitochondrial cristae formation [132].…”

Section: Crosstalk Between Apoptosis and Mptpmediated Necrosismentioning

confidence: 73%

“…A turning point in the field was the revelation that the F1F0 ATP synthase could function as a component of the mPTP pore in one of two ways, by passing solutes either through the border between two ATP synthase monomers or through the c-subunit ring that spans the inner mitochondrial membrane [127,128], but this remains controversial [129]. In two independent studies, highly purified ATP synthase complexes were recently confirmed to possess channel activity consistent with the biophysical characteristics of the mPTP, strongly supporting the identification of the ATP synthase as the sole component of the mPTP pore [130,131]. Further, monomeric complexes were sufficient to mediate mPTP-like channel activity [131], thus distinguishing the channel functions of ATP synthase monomers from the role of ATP synthase dimers in mitochondrial cristae formation [132].…”

Section: Crosstalk Between Apoptosis and Mptpmediated Necrosismentioning

confidence: 90%

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Double agents of cell death: novel emerging functions of apoptotic regulators

Lamb

2020

The FEBS Journal

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Apoptosis is a highly regulated form of cell death that is required for many homeostatic and pathological processes. Recently, alternative cell death pathways have emerged whose regulation is dependent on proteins with canonical functions in apoptosis. Dysregulation of apoptotic signaling frequently underlies the pathogenesis of many cancers, reinforcing the need to develop therapies that initiate alternative cell death processes. This review outlines the convergence points between apoptosis and other death pathways with the purpose of identifying novel strategies for the treatment of apoptosis-refractory cancers. Apoptosis proteins can play key roles in the initiation, regulation, and execution of nonapoptotic death processes that include necroptosis, autophagy, pyroptosis, mPTP-mediated necrosis, and ferroptosis. Notably, recent evidence illustrates that dying cells can exhibit biochemical and molecular characteristics of more than one different type of regulated cell death. Thus, this review highlights the amazing complexity and interconnectivity of cell death processes and also raises the idea that a top-to-bottom approach to describing cell death mechanisms may be inadequate for fully understanding the means by which cells die.

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Section: Crosstalk Between Apoptosis and Mptpmediated Necrosismentioning

confidence: 73%

Section: Crosstalk Between Apoptosis and Mptpmediated Necrosismentioning

confidence: 90%

Double agents of cell death: novel emerging functions of apoptotic regulators

Lamb

2020

The FEBS Journal

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“…Recently, two independent studies using purified F1F0ATP synthase from dog or pig heart respectively, proved more evidence on the essentialness of this enzyme on mPTP activity/structure. It has been shown that, under the Ca 2+ treatment, purified ATP synthase activity can be regulated by an mPTP specific agonist and inhibitor, and the purified monomer forms are in voltage-gated and Ca 2+ -activated channels [ 48 , 49 ]. A study points out that the sensitivity of pore opening varies according to the respiratory status and substrates availability [ 50 ].…”

Section: Mitochondrial Ca 2+ Uptake a Double-ementioning

confidence: 99%

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

Lai

Qiu

2020

IJMS

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Calcium ion (Ca2+) plays a critical role in the cardiac mitochondria function. Ca2+ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca2+ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca2+ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca2+ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca2+ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca2+ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca2+ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest.

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“…2,86], considerable experimental evidence can be adduced from studies on cell death [31,32,47−55]. These include numerous biochemical experiments [36,38,42,43,48−53], experiments based on electrophysiology on mitochondria [44−47], and several state-of-the-art electrophysiological experiments on the F O F 1 -ATP synthase in reconstituted systems [31,32]. The various experimental evidences that have been offered for the involvement of the ATP synthase in forming the PTP/MMC [for reviews, see refs.…”

Section: Experimental Evidence In Support Of the Hypothesis And Discumentioning

confidence: 99%

“…In addition to the central physiological function of the F O F 1 -ATP synthase as the energy currency in cell life, it has recently been proposed to be directly involved in the induction and permeability increase of mitochondria by the phenomenon of permeability transition (MPT) during apoptosis and cell death [31,32]. Following MPT, mitochondria cannot generate electrochemical ion gradients and therefore can no longer support the vital process of OXPHOS.…”

Section: Introductionmentioning

confidence: 99%

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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A mitochondrial megachannel resides in monomeric F1FO ATP synthase

Cited by 119 publications

References 63 publications

Double agents of cell death: novel emerging functions of apoptotic regulators

Double agents of cell death: novel emerging functions of apoptotic regulators

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

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

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