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Jared Rutter

Ass0ciate Professor of Biochemistry

B.S. Brigham Young University

Ph.D. University of Texas Southwestern Medical Center

Research

References

rutter@biochem.utah.edu

Jared Rutter's Lab Page

Jared Rutter's PubMed Literature Search

Research

My laboratory is interested in the reciprocal coupling of core metabolism with the remainder of cell and organismal physiology.  Metabolic and nutrient status elicit substantial effects on a wide array of cellular biologies, including cell growth, cell division, protein synthesis and many others.  Conversely, many cellular signaling pathways exert control on important metabolic decisions.  Our broad goal is to begin to understand how this crosstalk occurs in normal situations and how its impairment is involved in disease states (see Lindsley and Rutter, 2004).  Our research currently centers in three areas: First, we are examining the regulation and function of PAS kinase (PASK), a protein we think participates in this system by sensing nutrient status and conveying this signal to the machinery of metabolism, cell growth and cell division.  As a result, PASK is predicted to play an important role in diabetes, obesity and potentially cancer.  Second, we are examining a new system we have discovered that appears to be an important component of mitochondrial quality control.  We expect that this project will have impact on many aspects of human biology, including neurodegenerative disorders.  Third, we have initiated a broad program to understand the mysteries of mitochondria.  This has been a fruitful approach, with major discoveries in cancer, mitochondrial complex assembly and core metabolic processes.

PASK regulation: We have found that nutrient status regulates PASK activity both in mammalian and yeast cells.  Specifically, PASK is activated in cultured beta-cells grown in elevated glucose (daSilva Xavier, et al. 2004), likely as a result of increased mitochondrial metabolism.  Similarly, growth of yeast under conditions that require mitochondrial respiration (growth on non-fermentable carbon sources) also substantially activates PASK (Grose, et al. 2007).  This regulation likely interconnects with our recent and exciting observation that growth factor signaling activates PASK.  Using yeast, mammalian cells and mice as model systems, we are trying to identify the factors that regulate PASK, both transcriptionally and post-translationally.

PASK and mammalian energy homeostasis: Diabetes mellitus is rapidly becoming one of the predominant health concerns of the western world.  Fundamentally, diabetes is a failure of the insulin signaling system, which functions to maintain blood glucose concentrations within a narrow range. We have found that PASK is required for the synthesis of insulin in response to elevated glucose in cultured beta-cells.  We have extended these finding using mice wherein PASK has been deleted (Pask-/- mice).  These mice are hypoinsulinemic and as a result have an impaired ability to clear glucose after an injected glucose challenge.  Further, isolated beta-cells from Pask-/- mice have a profound defect in glucose-stimulated insulin secretion in vitro. However, PASK-/- mice were resistant to high-fat diet induced obesity, hepatic steatosis and insulin resistance.  This phenotype appears to be due to hypermetabolism in PASK-/- mice in vivo as measured by indirect calorimetry and in isolated skeletal muscle. These findings suggest an important physiological role of PASK in regulating metabolism and controlling energy balance in mammals (Hao, et al. 2007).

A major focus of our lab is to understand the mechanisms by which PASK controls both cellular and organismal energy metabolism.  Specifically, we are working to understand how PASK regulates mitochondrial metabolism in skeletal muscle (and probably in many cell types).  We are also working to understand how PASK controls hepatic lipid metabolism (as described in Hao, et al. 2007).  We have strong in vivo data, using genetics and pharmacology, that PASK plays a key role in mediating the effects of a Western diet to promote dyslipidemia and disease.

Mitochondria: It is increasingly apparent that mitochondria and their dysfunction lie at the heart of many human diseases.  These include type 2 diabetes, a number of neurodegenerative disorders, cancer and aging itself.  The understanding, prevention and treatment of these and other diseases requires a more complete understanding of how mitochondrial function, both in energy production and in cellular decisions, is regulated and maintained.
While much is known about mitochondria and their workings, much still awaits discovery.  This is illustrated by proteomics experiments, which show that more than 20% of mitochondrial proteins are essentially uncharacterized.  This includes a large number that are highly conserved throughout eukarya, a strong indication that they perform a fundamental and important function.  We have chosen to initiate studies to determine the genetic and biochemical function of thirty of these conserved mitochondrial proteins.  Each has been identified as mitochondrial, but has not been further studied.  Of the thirty, we have made substantial progress on understanding the function of six.  1) Sdh5 is a tumor suppressor that functions to promote the assembly of the succinate dehydrogenase complex (Hao, et al. 2009).  2) Vms1 is a component of a novel system for stress-responsive mitochondrial quality control (see below) (Heo, et al. 2010).  The other four have unpublished roles in pyruvate metabolism, electron transport chain supercomplex assembly, fatty acid oxidation and mitochondrial biogenesis. 

Mitochondrial quality control: Through our studies of Vms1 (Heo, et al. 2010), we discovered a stress-responsive system that promotes the degradation of mitochondrial proteins via the ubiquitin-proteasome system.  When this system is absent or defective, mitochondria become progressively dysfunctional and eventually lead to cell death.  This is strikingly similar to the progressive mitochondrial dysfunction that is observed in many age-related human diseases, particularly neurodegenerative disorders such as Parkinson’s disease.  We are trying to understand how this system works at a mechanistic, biochemical level using yeast, cultured cells and in vitro experiments.  We are also working to understand the importance of this system in mammalian physiology through the study of mouse models lacking Vms1. 

 

References