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.