Organelle membrane contact sites orchestrate inter-organelle communication that is essential for cellular homeostasis. However, aberrant crosstalk between lysosomes and mitochondria has been linked with neurodegenerative disease.

The lysosomal storage disease Niemann-Pick disease type C (NPC) is caused by loss of function mutations in the (LE/Lys) lipid transport proteins NPC1 or NPC2. The resulting accumulation of lysosomal lipids in NPC has complex downstream consequences including mitochondrial dysfunction, which is thought to be a key driver of disease pathogenesis. How a defect in a lysosomal lipid transport protein causes mitochondrial dysfunction is not fully understood, but we identified expanded mitochondria:lysosome contact sites (MLCs) in NPC1-deficient cells.

Membrane contact sites are regions where the membranes of neighbouring organelles are tethered in close proximity (typically 5-40nm apart) by protein and lipid complexes and are important sites of signaling and lipid and ion exchange. Our data suggest that MLCs are heavily influenced by the LE/Lys lipid environment, identifying a direct correlation between MLC extent and LE/Lys cholesterol levels. Expanded MLCs in NPC are associated with mitochondrial lipid accumulation, likely contributing to mitochondrial dysfunction, exacerbated by impaired removal of damaged mitochondria by mitophagy when MLCs are increased.

The lab is also exploring ER contact sites with lysosomes and lysosome-related organelles and applying findings from NPC to other diseases including Age-related Macular Degeneration and Parkinson’s Disease.