Molecular mechanisms underlying mitochondria-lysosome membrane contact sites in neuronal function and neurodegeneration

Both mitochondria and lysosomes are critical for regulating neuronal metabolism and function, and dysfunction of both organelles has been implicated in multiple neurodegenerative diseases including Parkinson’s and Charcot-Marie-Tooth (CMT) disease. However, the interplay between these two organelles in regulating neuronal homeostasis and driving neurodegeneration are still not well understood. Inter-organelle membrane contacts form between two different organelles and are critical sites for mediating organelle dynamics, metabolite exchange and signaling, but whether mitochondria and lysosomes form similar membrane contact sites to regulate their functional crosstalk was previously unknown. We identified the formation and regulation of mitochondria-lysosome membrane contact sites which represent a new pathway for the bidirectional regulation of mitochondria and lysosomes, but the roles of these contact sites in neurons and their contributions to neurodegeneration remain to be better elucidated. Importantly, further studying the neuronal role of mitochondria-lysosome contacts provides important insight into coupled mitochondrial and lysosomal function in neurons, and into potential pathways for their coupled dysfunction in multiple neurodegenerative diseases. In this project, we propose to investigate the molecular mechanisms underlying mitochondria-lysosome contact function in healthy and diseased neurons via advanced microscopy techniques including super-resolution imaging, electron microscopy and high spatial and temporal resolution live cell microscopy. In Aim 1, we will investigate how mitochondria-lysosome contacts regulate neuronal health and homeostasis by examining the role of contacts in regulating lipid homeostasis in mitochondria and lysosomes in neurons. Moreover, as lysosomal Rab7 GTP hydrolysis from GTP-bound state to GDP-bound state driven by a mitochondrial GAP (GTPase activating protein) regulates mitochondria-lysosome contact dynamics, disruption of Rab7 may contribute to neurodegeneration by misregulating contact dynamics and downstream lysosomal and mitochondrial function. In Aim 2, we will investigate the role of Rab7-mediated mitochondria-lysosome contact misregulation by specific genetic mutations linked to Parkinson’s disease and CMT, two neurodegenerative diseases which are linked to both mitochondrial and lysosomal dysfunction. Together, the proposed research will help uncover new mechanisms underlying disease pathogenesis at the intersection of inter-organelle contact sites and neurodegeneration.