Understanding the role of pyruvate metabolism-dependent signaling networks in the differentiation of neural stem cells

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Our cells need energy to function properly. There are two major pathways that can be used to generate energy in the form of ATP. Oxidative phosphorylation (OXPHOS), uses oxygen to drive the formation ATP. In the absence of oxygen, a pathway called glycolysis can break down glucose and generate ATP independently through a process called lactate fermentation. While OXPHOS can generate far more ATP than glycolysis, paradoxically, many highly active cells prefer to use glycolysis for energy production even when oxygen is available. This allows cells to use metabolic intermediates from the glycolytic pathway to synthesize cellular building blocks or modify proteins to change the way they transmit signaling messages. Therefore, cells need to `decide' when to sacrifice their ATP production to generate more metabolic precursors. Pyruvate lies at the bifurcation point between glycolysis and OXPHOS. Whether pyruvate feeds into the into the mitochondria to support OXPHOS or gets converted to lactate to maintain ongoing glycolysis is governed by the action of three main enzymes: the mitochondrial pyruvate carrier (MPC), pyruvate dehydrogenase (PDH), and lactate dehydrogenase (LDH). Although pyruvate fate represents a critical determination point in cellular energy production, the role of the pyruvate metabolic networks in regulating cellular communication and signaling mechanisms is not well understood. The brain utilizes 20% of the body's glucose and oxygen despite comprising only 2% of the body's mass. The brain is composed of a complex network of neurons and supporting cells, each with their own unique functions. These distinct cell types all arise from the differentiation of neural stem cells (NSCs), however, the metabolic preferences and metabolism-related signaling mechanisms that regulate NSC differentiation are unclear. Using cutting-edge techniques to generate `brains in a dish' we will study the metabolic changes that occur during NSC differentiation. We will also employ a small animal model using zebrafish, which represents an ideal model to study NSC differentiation because they contain populations of regenerative NSCs throughout their lifespan. Finally, we will use genetic engineering technologies to manipulate the MPC-PDH-LDH axis and to determine how changes in pyruvate metabolism impact neural differentiation into specific cell types. This research program represents a new emerging area of research focused on exploring the concept of metabolism as being a central regulator of multi-lineage NSC differentiation. Knowledge generated from this program will significantly advance the field of neuroscience and greatly enhance our understanding about the role of metabolism in regulating the neural stem cell niche and lineage-specific differentiation.