National Institute of General Medical Sciences 5R35GM147222-05

Cellular mechanisms of bioenergetic plasticity

This NIH grant funds research at Washington University to study how cells regulate energy metabolism at the subcellular level, focusing on neurons. The project uses advanced imaging and genomic techniques to understand metabolic plasticity and its role in diseases like diabetes and myopathies.

Description

Cellular mechanisms of bioenergetic plasticity. The long-term goal of our research program is to understand how cells fine-tune their metabolic programs to meet their ever-changing energetic needs. Many cell types in the body, from muscle fibers to neurons, have evolved unique metabolic programs that are essential for survival and proper function. Even within a single cell, specific processes are energetically coupled to mitochondria or the glycolytic machinery for specialized metabolic support. However, the underlying molecular basis of metabolic plasticity and its relationship to cellular function are poorly understood. Understanding the mechanisms of metabolic regulation is highly relevant to many disease states, including diabetes, myopathies, and Leigh syndrome, where metabolic dysfunction is heavily implicated. In eukaryotic cells, energy, in the form of ATP molecules, is primarily produced by glycolysis and mitochondrial oxidative phosphorylation. Our laboratory combines optical imaging of biosensors in live cells with genomics and transcriptomic analysis to investigate metabolic regulation in cellular compartments. With these tools, we have been able to discover novel pathways for stimulation of mitochondrial and glycolytic ATP production in active neurons during electrical activity. We now seek to understand how energy metabolism is locally regulated in subcellular compartments, and uncover metabolic specialization of functionally distinct neuronal types. To carry out this work, we plan to utilize our strength in cellular imaging of metabolic function along with new technological advances to: (1) determine how subcellular organization of the glycolytic machinery regulates synaptic vesicle endocytosis, and (2) elucidate molecular mechanisms of metabolic specialization using the available transcriptional profiles of neuronal subtypes. Our study will shed light on both local and global mechanisms of metabolic plasticity at the subcellular level and across cell types. As such, our findings will be broadly relevant to the scientific community studying cellular metabolism and its implications in disease states.

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