Grant: Project Grant

The control of cellular energy production is an area of intense investigation. The reason for this interest is that many devastating diseases, such as cancer, diabetes or various brain dysfunctions are now recognized as "metabolic diseases". This designation means that these diseases result from defects in the metabolic, chemical reactions that generate energy from "respiration" or breakdown of sugar within the cells of our organs. Because of this insight, cell biologists today investigate the mechanisms that control cellular me-tabolism with the aim to tweak or rescue the balance of cellular energy production in disease. Our laboratory works on an intracellular membrane structure that controls cellular metabolism. This struc-ture is called the mitochondria-associated membrane (MAM). The MAM is a very small site inside our cells where multiple "biomembranes" attach to each other. At the MAM, calcium- and chemical-based signals turn on respiration when energy becomes scarce. If this crosstalk is disrupted, energy production is shifted towards the breakdown of sugar, and this is a known signature of cancer. We have discovered a mechanism that allows the MAM to control cellular energy production. The MAM activates this mechanism when cells are stressed. Under this condition, a protein assembly forms that chemically modifies the MAM structure. We will investigate what is needed to form this assembly and how the proteins that make up the MAM react to these chemical modifications. We will then determine what our discoveries mean for metabolism in cancer tissue. Using cell culture models and tumor growth in animals, we will explore pharmacological strategies to control the MAM structure. The new insight we gain will explain how metabolic changes allow tumors to speed up growth and how this property may be eventually harnessed to control cancer.