The kidney proximal tubule is a highly specialized epithelium that transports metabolites and maintains body homeostasis. Cells lining this nephron segment are densely packed with lysosomes, but little is known about the dynamic activity of these organelles in situ. Here, using targeted sensors and live cell and intravital imaging we track acidified lysosomes along the mouse proximal tubule and uncover marked axial heterogeneity in their distribution, characteristics and organellar interactions. In the early part, cathepsin-rich lysosomes frequently contact with apical endosomes to receive and catabolize filtered plasma proteins. Conversely, in the later region, lipase-containing lysosomes traverse cells to mobilize and degrade mitochondria-associated lipid droplets and facilitate their extrusion into the tubular lumen. Acutely de-acidifying lysosomes dramatically alters their movement, causing major changes in tubular protein and lipid processing. Thus, lysosomes in proximal tubules are highly dynamic and adapted to perform distinct metabolic tasks within different specialized segments.
© 2026. The Author(s).