What are the roles of V-ATPases in membrane fusion?

Merz, Alexey J.

doi:10.1073/pnas.1422280112

Cited by 12 publications

(8 citation statements)

References 33 publications

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“…A high H + concentration inside an inverted micelle core may force protons through the two halves of the F 0 channel of the ATP synthase complex, a hypothetical structure of which has been previously described [1, 12]. Furthermore, this inverted micelle connecting two adjacent IMM may be an intermediate step that facilitates membrane fusion in a similar fashion as mediated by V-ATPases [51].…”

Section: 0 Discussionmentioning

confidence: 99%

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

Gasanov

Kim

Yaguzhinsky

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

105

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Cardiolipin (CL) is an anionic phospholipid at the inner mitochondrial membrane (IMM) that facilitates the formation of transient non-bilayer (non-lamellar) structures to maintain mitochondrial integrity. CL modulates mitochondrial functions including ATP synthesis. However, the biophysical mechanisms by which CL generates non-lamellar structures and the extent to which these structures contribute to ATP synthesis remain unknown. We hypothesized that CL and ATP synthase facilitate the formation of non-bilayer structures at the IMM to stimulate ATP synthesis. By using H NMR andP NMR techniques, we observed that increasing the temperature (8°C to 37°C), lowering the pH (3.0), or incubating intact mitochondria with CTII - an IMM-targeted toxin that increases the formation of immobilized non-bilayer structures - elevated the formation of non-bilayer structures to stimulate ATP synthesis. The F sector of the ATP synthase complex can facilitate the formation of non-bilayer structures as incubating model membranes enriched with IMM-specific phospholipids with exogenous DCCD-binding protein of the F sector (DCCD-BPF) elevated the formation of immobilized non-bilayer structures to a similar manner as CTII. Native PAGE assays revealed that CL, but not other anionic phospholipids, specifically binds to DCCD-BPF to promote the formation of stable lipid-protein complexes. Mechanistically, molecular docking studies identified two lipid binding sites for CL in DCCD-BPF. We propose a new model of ATP synthase regulation in which CL mediates the formation of non-bilayer structures that serve to cluster protons and ATP synthase complexes as a mechanism to enhance proton translocation to the F sector, and thereby increase ATP synthesis.

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Section: 0 Discussionmentioning

confidence: 99%

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

Gasanov

Kim

Yaguzhinsky

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

105

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“…Thus more efficient membrane fusion may occur in regions in which the holoenzyme has been disassembled. Some studies have indeed implicated the V O sector in membrane fusion, but this hypothesis remains controversial ( 43 , 56 ).…”

Section: Regulation Of V-atp Ase Activitymentioning

confidence: 99%

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Eaton

Merkulova

Brown

2021

American Journal of Physiology-Cell Physiology

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A primary function of the H+-ATPase (or V-ATPase) is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes. Its activity notably allows for the acidification of intracellular vesicles and organelles, which is necessary for many essential cell biological events to occur. In addition, many specialized cell types in various organ systems such as the kidney, bone, male reproductive tract, inner ear, olfactory mucosa, and more, use plasma membrane V-ATPases to perform specific activities that depend on extracellular acidification. However, it is increasingly apparent that V-ATPases are central players in many normal and pathophysiological processes that directly influence human health in many different, and sometimes unexpected ways. These include cancer, neurodegenerative diseases, diabetes, and sensory perception, as well as energy and nutrient sensing functions within cells. This review first covers the well-established role of the V-ATPase as a transmembrane proton pump in the plasma membrane and intracellular vesicles, and outlines factors contributing to its physiological regulation in different cell types. This is followed by a discussion of the more recently emerging unconventional roles for the V-ATPase, such as its role as a protein interaction hub involved in cell signaling, and the (patho)physiological implications of these interactions. Finally, the central importance of endosomal acidification and V-ATPase activity on viral infection will be discussed in the context of the current COVID-19 pandemic.

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“…BafA1 is a widely used powerful inhibitor of the vacuolar class H + -ATPases (V-ATPase; IC 50 = 4–400 nM), which blocks acidification of endosomes, lysosomes and phagosomes by arresting proton pumping from the cytosol [ 31 ]. Reportedly BafA1 also inhibits endosome-endosome or autophagosome-endosome/lysosome fusion, which may occur independently of the V-ATPase inhibition and, hence, compartment alkalinization [ 32 – 36 ]. Concordantly, deacidification of membrane organelles by weak bases such as chloroquine or NH 4 Cl is ineffective in preventing the vacuolization triggered by PIKfyve inhibition with YM201636, suggesting that BafA1 protects and reverses the aberrant endomembrane dilation by a mechanism that counteracts endosomal fusion [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

Sbrissa¹,

Naisan²,

Ikonomov³

et al. 2018

PLoS ONE

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PIKfyve, an evolutionarily conserved kinase synthesizing PtdIns5P and PtdIns(3,5)P2, is crucial for mammalian cell proliferation and viability. Accordingly, PIKfyve inhibitors are now in clinical trials as anti-cancer drugs. Among those, apilimod is the most promising, yet its potency to inhibit PIKfyve and affect endomembrane homeostasis is only partially characterized. We demonstrate here for the first time that apilimod powerfully inhibited in vitro synthesis of PtdIns5P along with that of PtdIns(3,5)P2. HPLC-based resolution of intracellular phosphoinositides (PIs) revealed that apilimod triggered a marked reduction of both lipids in the context of intact cells. Notably, there was also a profound rise in PtdIns3P resulting from arrested PtdIns3P consumption for PtdIns(3,5)P2 synthesis. As typical for PIKfyve inhibition and the concomitant PtdIns(3,5)P2 reduction, apilimod induced the appearance of dilated endomembrane structures in the form of large translucent cytoplasmic vacuoles. Remarkably, bafilomycin A1 (BafA1) fully reversed the aberrant cell phenotype back to normal and completely precluded the appearance of cytoplasmic vacuoles when added prior to apilimod. Inspection of the PI profiles ruled out restoration of the reduced PtdIns(3,5)P2 pool as a molecular mechanism underlying BafA1 rescue. Rather, we found that BafA1 markedly attenuated the PtdIns3P elevation under PIKfyve inhibition. This was accompanied by profoundly decreased endosomal recruitment of fusogenic EEA1. Together, our data demonstrate that apilimod inhibits not only PtdIns(3,5)P2 but also PtdIns5P synthesis and that the cytoplasmic vacuolization triggered by the inhibitor is precluded or reversed by BafA1 through a mechanism associated, in part, with reduction in both PtdIns3P levels and EEA1 membrane recruitment.

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What are the roles of V-ATPases in membrane fusion?

Cited by 12 publications

References 33 publications

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

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What are the roles of V-ATPases in membrane fusion?

Cited by 12 publications

References 33 publications

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

Non-bilayer structures in mitochondrial membranes regulate ATP synthase activity

The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

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The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease