DNA nanodevices detect an acidic nanolayer on the lysosomal surface

doi:10.1038/s41556-025-01855-y

DNA nanodevices detect an acidic nanolayer on the lysosomal surface

2026-01-21

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DOI：10.1038/s41556-025-01855-y

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Lysosomes maintain a highly acidic lumen to regulate H+-dependent hydrolase-mediated degradation, but how protons are ‘leaked’ out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2–0.7 pH units more acidic than the neutral cytosol. This acidic nanolayer is established and maintained primarily by TMEM175, a lysosomal H+ efflux channel associated with Parkinson’s disease. Activation of TMEM175 causes opposite pH changes on both sides of lysosomes; however, it is the juxta-lysosomal, not the luminal, acidity that determines lysosome positioning in cells with dynein adaptor RILP acting as a juxta-lysosomal pH sensor. Hence, through inside-out proton conduits, lysosomes create a steady acidic surrounding that acts as a nano-interface for cytosolic machineries to regulate organellar activities. Tan and colleagues develop DNA nanodevices to detect the pH of the lysosomal outer surface, observing an acidic layer generated by TMEM175 that regulates lysosome positioning in response to changes in juxta-lysosomal pH.

Keywords:

lysosome

pH regulation

TMEM175

DNA nanodevices

juxta-lysosomal acidity

DNA nanodevices detect an acidic nanolayer on the lysosomal surface

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