Lysosomes are membrane-bound organelles whose acidic lumen (pH 4.5-5.0) is required for degradation. This luminal acidity is known to regulate cytosolic-side functions such as membrane fusion/fission, movement, and membrane-contact site formation.
However, how luminal acidity information is relayed to cytosolic effectors has been elusive, and the spatiotemporal profile of any juxta-lysosomal pH (pHjx-LY) signal remains unknown. The lack of tools to measure pHjx-LY is a major obstacle, as research has focused almost exclusively on intralysosomal pH (pHi-LY).
In a study published in Nature Cell Biology on January 21, a team led by Prof. TAN Weihong and Prof. QIU Liping from Hangzhou Institute of Medicine of Chinese Academy of Sciences, along with Prof. XU Haoxing from Zhejiang University, developed ratiometric DNA nanodevices stably anchored on the cytosolic leaflet membranes of lysosomes, which can quantitatively measure pHjx-LY in live cells.
Researcher found that a steady acidic layer with a thickness of up to 21 nm existed on the outer surface of all lysosomes, and the lysosomal H+ efflux channel TMEM175 was required to establish and maintain this acidic nanolayer. They revealed that it was pHjx-LY, but not pHi-LY, which mediated TMEM175-dependent, nutrient-sensitive regulation of lysosomal movement and distribution.
Moreover, researchers identified the adaptor protein RILP, which connects Rab7 to dynein motors, as a juxta-lysosomal pH sensor mediating retrograde lysosome transport.
In Parkinson's disease models, lysosomes in the soma exhibited a significantly more acidic pHjx-LY, showing a potential link to neurodegenerative pathogenesis. Besides, an intensified acidic nanolayer on the lysosomal surface promoted the formation of membrane contact sites between lysosomes and the endoplasmic reticulum, providing a new regulation mechanism on organellar interactions.
This study uncovers the existence and functional significance of the pHjx-LY nanolayer, and provides a mechanism for the luminal acidity to regulate key cytosolic-side functions. It opens up new avenues for therapeutic interventions targeting organelle-related pathologies.
