Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore

Urbani, Andrea; Giorgio, Valentina; Carrer, Andrea; Franchin, Cinzia; Arrigoni, Giorgio; Jiko, Chimari; Abe, Kazuhiro; Maeda, Shuichi; Shinzawa‐Itoh, Kyoko; Bogers, Janna F.M.; McMillan, Duncan G. G.; Gerle, Christoph; Szabó, Ildikò; Bernardi, Paolo

doi:10.1038/s41467-019-12331-1

Cited by 150 publications

(188 citation statements)

References 68 publications

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“…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: 89%

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: 89%

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

Lamb

2020

The FEBS Journal

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“…A self-standing field concerns with the mitochondrial permeability transition pore (mPTP), largely dependent on calcium homeostasis. Recently, mPTP was suggested to act as a non-physiological specific conformation of the ATP synthase and its oligomers [53]. However, this topic is beyond the scope of this review.…”

Section: The Interplay Between Ros Mitochondrial Anion Channels Andmentioning

confidence: 94%

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

2020

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Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.

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“…Opening of this pore leads to mitochondrial dysfunction and cell death by either apoptosis or necrosis (53). Recent work on the components of the mPTP has implicated the c ring of the ATP synthase (56,57), a channel inside ATP synthase dimers (55,58), or the purified ATP synthase itself (59), as forming the pore. Interestingly, vestigial ATP synthases devoid of c subunits maintain mPTP formation features, suggesting that the c ring per se is not the channel (60).…”

Section: Specific Interaction Between Hsmcu and Hsatpc In Vitro And Imentioning

confidence: 99%

The Mitochondrial Calcium Uniporter Interacts with Subunit c of the ATP Synthase of Trypanosomes and Humans

Huang

Docampo

2020

mBio

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Mitochondrial Ca2+ transport mediated by the uniporter complex (MCUC) plays a key role in the regulation of cell bioenergetics in both trypanosomes and mammals. Here we report that Trypanosoma brucei MCU (TbMCU) subunits interact with subunit c of the mitochondrial ATP synthase (ATPc), as determined by coimmunoprecipitation and split-ubiquitin membrane-based yeast two-hybrid (MYTH) assays. Mutagenesis analysis in combination with MYTH assays suggested that transmembrane helices (TMHs) are determinants of this specific interaction. In situ tagging, followed by immunoprecipitation and immunofluorescence microscopy, revealed that T. brucei ATPc (TbATPc) coimmunoprecipitates with TbMCUC subunits and colocalizes with them to the mitochondria. Blue native PAGE and immunodetection analyses indicated that the TbMCUC is present together with the ATP synthase in a large protein complex with a molecular weight of approximately 900 kDa. Ablation of the TbMCUC subunits by RNA interference (RNAi) significantly increased the AMP/ATP ratio, revealing the downregulation of ATP production in the cells. Interestingly, the direct physical MCU-ATPc interaction is conserved in Trypanosoma cruzi and human cells. Specific interaction between human MCU (HsMCU) and human ATPc (HsATPc) was confirmed in vitro by mutagenesis and MYTH assays and in vivo by coimmunoprecipitation. In summary, our study has identified that MCU complex physically interacts with mitochondrial ATP synthase, possibly forming an MCUC-ATP megacomplex that couples ADP and Pi transport with ATP synthesis, a process that is stimulated by Ca2+ in trypanosomes and human cells. IMPORTANCE The mitochondrial calcium uniporter (MCU) is essential for the regulation of oxidative phosphorylation in mammalian cells, and we have shown that in Trypanosoma brucei, the etiologic agent of sleeping sickness, this channel is essential for its survival and infectivity. Here we reveal that that Trypanosoma brucei MCU subunits interact with subunit c of the mitochondrial ATP synthase (ATPc). Interestingly, the direct physical MCU-ATPc interaction is conserved in T. cruzi and human cells.

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Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore

Cited by 150 publications

References 68 publications

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

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

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

The Mitochondrial Calcium Uniporter Interacts with Subunit c of the ATP Synthase of Trypanosomes and Humans

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