# ATP13A2-Mediated Spermine Export Modulates Lipid Catabolism in the Endolysosomal System of SH-SY5Y Cells

## TL;DR

This study shows that ATP13A2, a transporter in cells, affects lipid digestion by moving spermine, a polyamine, from lysosomes to the cytosol, influencing lipid metabolism in SH-SY5Y cells.

## Contribution

The study reveals a novel functional link between polyamine transport and lipid catabolism in the endolysosomal system.

## Key findings

- ATP13A2-expressing cells showed higher ABHD6 expression and spermine-induced translocation to the cytoplasm.
- Spermine treatment increased ACase activity transiently but led to stronger inhibition in ATP13A2-expressing cells.
- GCase activity was elevated in ATP13A2-expressing cells but also showed greater spermine-induced inhibition.

## Abstract

Dysfunction of the membrane transporter P5B-ATPase 13A2 (ATP13A2) has been linked to neurodegenerative disorders, while its overexpression has been associated with colorectal cancer. ATP13A2 localizes to lysosomes and late endosomes, where it exports polyamines such as spermine into the cytosol. We previously showed that ATP13A2 expression alters lipid homeostasis and reduces the levels of bis(monoacylglycero)phosphate (BMP), an anionic phospholipid essential for lipid digestion in acidic compartments, suggesting that ATP13A2-mediated spermine export may affect lysosomal lipid catabolism. α/β-hydrolase domain-containing 6 (ABHD6), the enzyme responsible for BMP catabolism, was detected by immunofluorescence and immunoblot analysis in SH-SY5Y cells overexpressing human ATP13A2 and treated with spermine. The activities of the lipid-degrading hydrolases acid ceramidase (ACase) and glucocerebrosidase (GCase) were measured using specific fluorogenic substrates. ATP13A2-expressing cells showed higher ABHD6 expression, and spermine treatment promoted its translocation to the cytoplasm. Spermine induced a transient increase in ACase activity, followed by a stronger inhibition in ATP13A2-expressing cells. Moreover, GCase activity was elevated in these cells but also showed greater spermine-induced inhibition. Altogether, these results suggest that ATP13A2-mediated spermine export modulates the lipid digestion capacity of the endolysosomal system and support a functional interplay between polyamine and lipid metabolism in these organelles.