Deficient de-S-acylation in aging and CLN1 contributes to lyso-mitochondrial dysfunction, lipid dyshomeostasis, and resultant lipofuscin biogenesis.

Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and report the spatiotemporal dynamics of lipofuscin accumulation in aging and NCL in a murine neuroanatomical atlas. Multimodal mass spectrometry, ultrastructural analyses, and assays of metabolic flux identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and NCL.