The Rutter Lab currently explores three areas. While distinct, these programs are all centered upon cellular metabolic homeostasis—the concept that cells must constantly monitor their nutrient, metabolic and hormonal environments and adjust their behavior accordingly. This includes the decision to grow and proliferate, which goes awry in cancer.
- First, as much of metabolic control is enacted at the level of mitochondria—in ways that are mostly not understood—we initiated a project to functionally annotate the eukaryotic mitochondrial proteome. To date, this effort has elucidated the genetic basis of two human diseases, including a familial cancer syndrome and a metabolic disorder, and several fundamental mitochondrial functions.
- Second, we have developed and validated an experimental platform for the identification of low affinity protein-metabolite interactions. It has enabled discovery of novel metabolite-based allostery, which is the primary ancestral and acute modality for metabolic control.
- Finally, the discovery of conserved metabolic effectors and allosteric regulation culminate in our efforts on an ancient and allosterically regulated control circuit centered on the nutrient sensing PASK protein kinase, which plays an evolutionarily conserved role in partitioning available carbon between its various fates.
Mitochondria are small but complex organelles with a disproportionately large impact on human health. Changes in mitochondrial enzyme activities, respiratory capacity, genome sequence and superoxide generation play important roles in the pathogenesis of heart failure, cancer, neurodegenerative disorders such as Parkinson's, Alzheimer's and Huntington's disease and in aging and longevity.
We have a growing but incomplete understanding of the mechanisms whereby the body senses its nutrient status and responds to adapt cellular and organismal behavior accordingly. The resulting energetic efficiencies are of obvious evolutionary importance as organisms faced a variety of challenging environmental situations, including prolonged exertion, episodic food shortage and competition for resources.
Our biochemistry textbooks are filled with examples of allosteric regulation of metabolic enzymes by small molecule metabolites. Herein, I will use the term "allostery" to refer specifically to that subset of allosteric interactions wherein a small molecule regulates a protein by binding at a site other than an enzyme active site. These interactions are a fundamental component of homeostatic metabolic control, but also enable the cell to be agile in response to a changing environment.