CAREER: Advancing Proximity Labeling Mass Spectrometry to Characterize Neuronal Mitochondrial Dynamics

About This Grant

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Ling Hao from George Washington University is developing novel bioanalytical chemistry methods to study mitochondrial dynamics in human neurons. Mitochondria are the powerhouses of the cell; they produce ATP and function as hubs for many metabolic pathways. Neurons in the brain rely heavily on mitochondrial functions because have extremely high energy demands to support synaptic activities. However, the specific molecular microenvironment of neuronal mitochondria is not fully understood, partly due to technological limitations. This project will develop mass spectrometry (MS)-based techniques to characterize the dynamic mitochondrial activities and interactions at the molecular level in human, stem cell-derived neurons. Through partnership with local chemistry instrument companies and MS discussion group, a summer MS workshop will be organized to bring together students from different levels as well as scientists from local academic, industry, and government institutions. A set of research, education and outreach activities will be integrated to enhance student learning and training experiences at the university and regional levels and to promote accessibility and diversity in STEM (science, technology, engineering and mathematics). The proposed research aims to address major technical challenges and knowledge gaps to study molecular networks and the subcellular microenvironment in human neurons using mass spectrometry (MS) techniques. Despite the advancements in understanding mitochondrial functions, it is technically challenging to capture the dynamic mitochondrial microenvironment, particularly in neurons with highly polarized structures. A set of MS-based proximity labeling strategies will be developed to study mitochondrial activities, functions, metabolic regulations, and membrane dynamics in human induced pluripotent stem cells (iPSCs)-derived neurons. This research program will provide widely applicable chemistry tools to study sub-cellular biological microenvironment as well as provide new insights into mitochondrial dynamics and neurobiology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.