PROJECT SUMMARY Both mitochondria and lysosomes are critical for health and homeostasis, and dysfunction of both organelles has been implicated in multiple neurodegenerative diseases. However, the crosstalk between these two organelles in driving disease pathogenesis is still not well understood. Inter-organelle membrane contacts form between different organelles and are critical sites for modulating organelle dynamics and function. Mitochondria and lysosomes can form such inter-organelle contact sites, and their crosstalk at mitochondria- lysosome contacts represents a key pathway for the bidirectional regulation of mitochondria and lysosomes. Importantly, further studying the role of mitochondria-lysosome contacts may provide important insights into the regulation of mitochondrial and lysosomal function, and their contribution to the etiology of different neurological disorders. This research project will investigate the role of mitochondria-lysosome contact site misregulation in specific neurodegenerative diseases using advanced time-lapse microscopy. Ultimately, the proposed research will help uncover new mechanisms underlying disease pathogenesis at the intersection of inter-organelle contact sites and neurodegeneration.