Updated project metadata. Lysosomal storage diseases (LSDs) comprised ~50 gene loci causing the accumulation of cellular material in the lysosome and associated defects in lysosomal function, but systematic molecular phenotyping is lacking. Here, we apply a nanoflow-based multi-omic single-shot technology (nMOST) workflow to simultaneously quantify HeLa cell proteomes and lipidomes from dozens of LSD mutants, revealing diverse molecular phenotypes. Defects in delivery of ferritin and its autophagic regulator NCOA4 to lysosomes (ferritinophagy) were pronounced in NPC2-/- cells, which correlated with increased lyso-phosphatidyl-choline species and dramatic multi-lamellar membrane structures visualized by cryo-electron tomography. Ferritinophagy defects correlated with loss of mitochondrial cristae, MICOS complex components, and electron transport chain complexes rich in iron-sulfur cluster proteins. Strikingly, these defects were rescued when iron was provided through the transferrin system. This resource reveals how loss of lysosomal function impacts organelle homeostasis in trans and highlights nMOST profiling as a discovery tool for illuminating distinct molecular phenotypes across LSDs.