Abnormal lipid remodeling of a lysosomal storage disease

Lysosomes are integral organelles that communicate cellular status to an entire tissue through mechanisms that are poorly defined. We developed an unbiased platform, integrating human plasma metabolomes and single lysosome metabolomics, and show that the by-products of proteolysis are an unexpected class of signaling molecules. We show that dimethylarginine is a lysosomal-derived metabolite and predictor of patient morbidity. Genetic depletion of a lysosomal exporter, cystinosin, resulted in the accumulation of dimethylarginine in lysosomes. Leveraging a lysosomal storage disease with cystinosin mutations, we show that the rapid plasticity of dimethylarginine compartmentalization ensures cell and tissue homeostasis. Strikingly, lysosomal entrapment of dimethylarginine in patients and disease models corresponds with lipid accumulation, lipid droplets, and lipotoxicity. Exogenously restoring asymmetric dimethylarginine buffers oxidative stress, decreasing lipid peroxidation and cell death. These data show dimethylarginine engages an inter-organellar process–with peroxisomes, lysosomes, and lipid droplets–that confers a crucial adaptive response mechanism.