Life, as we know it, is a dynamic network of metabolic reactions that take nutrients from the environment and convert them into the building blocks and energy that cells need to grow and function. Each cell has a unique set of biosynthetic and energetic demands that must be met to ensure normal homeostasis. As a result, cells must establish distinct metabolic states to meet those demands. Disruption of these mechanisms can lead to severe developmental disorders and promote the progression of diseases such as cancer, neurodegeneration, and reproductive disorders.
Our primary goal in the lab is to understand the dynamic changes in metabolic programs that support developmental and disease progression. Using a combination of genetics, molecular biology, and system based approaches (metabolomics, proteomics, and transcriptomics) we are investigating metabolic mechanisms that support reproduction and development in Drosophila and mammalian tissues. Our work focuses on three key areas:
Understanding the role of metabolism in cellular quiescence
During development, many cells such as oocytes, spores, seeds, muscle satellite cells, and certain types of immune cells, reduce their transcription and translation and enter a state of cellular quiescence. During this process, cells reduce their overall metabolic activity as means to protect the cell from oxidative damage and to maintain stored nutrients. However, the mechanisms that mediate these effects on metabolism during quiescence remain unclear. Using the Drosophila ovariole system we have found that a decrease in Insulin/Akt signaling triggers a remodeling of the mitochondria that promotes mitochondrial respiratory quiescence in mature oocytes. This effect is mediated by the conserved Akt target GSK3, which triggers a massive shift in the mitochondrial proteome. We are currently investigating the molecular mechanisms downstream of GSK3 that mediate remodeling of the mitochondrial proteome and induce mitochondrial respiratory quiescence.
Interestingly upon fertilization oocytes reactivate their mitochondria and increase their overall metabolic activity as a means to support the growth and development of the early embryo. Furthermore, We have found similar shifts in mitochondrial metabolism occur in developing mammalian tissues suggesting that dynamic changes in mitochondrial function may be a conserved aspect of quiescence and reactivation in many species. Despite these observations surprisingly little is known about the mechanism that underlies metabolic reactivation after quiescence. Our goal is to define these conserved mechanisms that mediate mitochondrial reactivation and to ascertain specific biosynthetic and energetic roles mitochondrial reactivation plays during development.
Examining how mitochondrial metabolism impacts growth and differentiation
As cells progress through phases of growth and differentiation the biosynthetic and energetic demands change drastically. As a result, mitochondrial metabolism must be altered to provide the building blocks for growth or, in contrast, create a metabolic state that supports differentiation. While there are clear metabolic programs (aerobic glycolysis/ Warburg metabolism) that support growth; the metabolic mechanisms that support other aspects of development such as cell migration, morphogenesis, and differentiation remain unclear. Our goal is to define the dynamic transitions in mitochondrial metabolism that occur during development and determine what role they may play in specific developmental stages.
The Drosophila ovariole system provides an ideal system for the study of metabolism during development. Each ovariole functions as an assembly line for egg development, providing a system to easily isolate ample quantities of precisely staged oocytes to use in studies of mitochondrial function and for use in systems based approaches like metabolomics and proteomics. Interestingly we, and others, have found that nutrients accumulate in a precise stepwise manner during oogenesis. Amino acids in the form of yolk protein begin to accumulate during stage 8 of oogenesis. This followed by massive storage of neutral lipids (triglycerides and sterol esters) during stage 9-10 of oogenesis. After lipid storage is complete there is a massive 40 fold increase in stored glycogen, caused in part by reducing mitochondrial activity, that occurs between stages 12-14 of oogenesis. Using this system we are investigating the molecular mechanisms that mediate these changes in metabolic state during oogenesis. Furthermore, using cell culture and the mouse model we are also examining the conserved roles of specific aspects of mitochondrial metabolism in vertebrate tissue development.
Investigating how cellular metabolism regulates developmental signaling pathways
Developing organisms must integrate cues from the environment (nutrients, environmental stresses, etc.) with genetically encoded developmental signaling pathways. For example, in yeast, nitrogen and glucose deprivation induces sporulation and meiosis. In contrast, in the worm C.elegans, nutrient deprivation during development induces an alternative developmental program called dauer that protects the animal under harsh conditions. However, the regulation of developmental processes by specific metabolic mechanisms remains unclear in many systems.
Using a combination of Drosophila genetics and mammalian cell culture we have found that specific lipid metabolites and metabolic pathways can greatly influence the activity of developmental signaling pathways in both flies and mammalian tissue. These metabolic effects on developmental signaling pathways can influence many aspects of development ranging from cell fate decisions to progression through developmental checkpoints. We’re currently studying how lipid metabolites can directly influence cell fate decisions through regulation of developmental signaling pathways and whether this is a conserved aspect of tissue development in many species.
Rotation projects for 2021:
- Conducting metabolomic analysis to understand how metabolic reprogramming impacts redox balance in response to maternal metabolic stress.
- Determining how mitochondrial metabolism regulates differentiation by controlling receptor trafficking.
- Investigating how fatty acid oxidation regulates proteasome function and cytosolic proteostasis.