Cellular mechanisms of bioenergetic plasticity

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. My 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.

Grant Number: 5R35GM147222-04
NIH Institute/Center: NIH
Principal Investigator: Ghazaleh Ashrafi