Regulation of the mammalian-brain V-ATPase through ultraslow mode-switching

Eleftherios Kosmidis, Christopher G. Shuttle, Julia Preobraschenski, Marcelo Ganzella, Peter J. Johnson, Salome Veshaguri, Jesper Holmkvist, Mads P. Møller, Orestis Marantos, Frank Marcoline, Michael Grabe, Jesper L. Pedersen, Reinhard Jahn and Dimitrios Stamou ()
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Eleftherios Kosmidis: University of Copenhagen
Christopher G. Shuttle: University of Copenhagen
Julia Preobraschenski: Max Planck Institute for Multidisciplinary Sciences
Marcelo Ganzella: Max Planck Institute for Multidisciplinary Sciences
Peter J. Johnson: University of Copenhagen
Salome Veshaguri: University of Copenhagen
Jesper Holmkvist: University of Copenhagen
Mads P. Møller: University of Copenhagen
Orestis Marantos: University of Copenhagen
Frank Marcoline: University of California San Francisco
Michael Grabe: University of California San Francisco
Jesper L. Pedersen: University of Copenhagen
Reinhard Jahn: Max Planck Institute for Multidisciplinary Sciences
Dimitrios Stamou: University of Copenhagen

Nature, 2022, vol. 611, issue 7937, 827-834

Abstract: Abstract Vacuolar-type adenosine triphosphatases (V-ATPases)1–3 are electrogenic rotary mechanoenzymes structurally related to F-type ATP synthases4,5. They hydrolyse ATP to establish electrochemical proton gradients for a plethora of cellular processes1,3. In neurons, the loading of all neurotransmitters into synaptic vesicles is energized by about one V-ATPase molecule per synaptic vesicle6,7. To shed light on this bona fide single-molecule biological process, we investigated electrogenic proton-pumping by single mammalian-brain V-ATPases in single synaptic vesicles. Here we show that V-ATPases do not pump continuously in time, as suggested by observing the rotation of bacterial homologues8 and assuming strict ATP–proton coupling. Instead, they stochastically switch between three ultralong-lived modes: proton-pumping, inactive and proton-leaky. Notably, direct observation of pumping revealed that physiologically relevant concentrations of ATP do not regulate the intrinsic pumping rate. ATP regulates V-ATPase activity through the switching probability of the proton-pumping mode. By contrast, electrochemical proton gradients regulate the pumping rate and the switching of the pumping and inactive modes. A direct consequence of mode-switching is all-or-none stochastic fluctuations in the electrochemical gradient of synaptic vesicles that would be expected to introduce stochasticity in proton-driven secondary active loading of neurotransmitters and may thus have important implications for neurotransmission. This work reveals and emphasizes the mechanistic and biological importance of ultraslow mode-switching.

Date: 2022
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DOI: 10.1038/s41586-022-05472-9

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