Professor of Biochemistry
B.S. Brigham Young University
Ph.D. University of Texas Southwestern Medical Center
Jared Rutter's Lab Page
Jared Rutter's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Cancer metabolism, Diabetes & obesity, Metabolic signaling
My laboratory is currently exploring 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. 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 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—not discussed in detail . 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. Using both broad and deep approaches, our goal is to define the molecules and their interactions that enable robust and responsive cellular metabolic control. The projects described below are examples of the questions we ask and the approaches we take to ask them, but we are always looking for new ways to understand metabolism and how it integrates with cell behavior.
Functional Annotation of the Mitochondrial Proteome
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. The best current inventory of mammalian mitochondrial resident proteins consists of 1098 proteins . Surprisingly, nearly 300 of these proteins are uncharacterized . This includes many that are highly conserved throughout eukarya, a strong indication that they perform a fundamentally important function. The genes that encode the mitochondrial proteome are heavily represented amongst known human disease genes, with about 20% of predicted human mitochondrial proteins implicated in one or more hereditary diseases [3,4]. Presumably, the quarter of the mitochondrial proteome that is uncharacterized contains many others that await discovery. Making this connection would be greatly facilitated by an understanding of the genetic connections, biochemical properties and physiological functions of these proteins. Therefore, elucidating the functions of these uncharacterized, conserved mitochondrial proteins will not only explain important aspects of mitochondrial biology, but will also provide a framework for identifying new human disease genes.
As a first step toward this goal, we bioinformatically identified many mitochondrial protein families that are pan-eukaryotic and unstudied. Using yeast mutants generated in our lab, we have analyzed the loss-of-function growth phenotypes for each. We have also determined the subcellular and sub-mitochondrial localization for each protein. Such higher throughput, standardized studies have then been used to guide specific hypotheses for a subset of proteins. These projects, all focused on proteins for which no function had ever been described, have progressed to various levels of understanding; six are published.
We have recently discovered  that the mitochondrial pyruvate carrier complex is preferentially lost in a wide variety of cancers and that this suppression is a critical feature of establishing the aberrant metabolic profile typical of cancer, known as the Warburg effect. When MPC1 and MPC2 are re-expressed in cancer cells, their metabolism reverts to that typical of normal cells. Those cells also lose the ability to grow in tumor-like situations, including in xenograft assays. This is likely due to the fact that MPC expression causes a loss of stem cell markers and functions.
These studies have led to the initiation of a significant effort in the lab to understand the fundamental metabolic underpinnings of cancer and stem cells. We are employing in vitro and in vivo systems in conjunction with biochemical, genetic, metabolomic and cell biological approaches.
In summary, our goal to functionally annotate the mitochondrial proteome has enabled discovery of biochemical functions important for mitochondria, elucidation of the genetic basis of two human diseases and catalysis of future studies with a direct impact on common human diseases. In addition to the six projects described above, we are actively pursuing the functions of a number of additional protein families.
Integrated Control of Metabolism by PASK-dependent Signaling
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. In modern human societies, however, these adaptations often have negative health consequences. One clear example is the propensity of most mammals to store excess ingested calories, primarily as fat, in anticipation of an ensuing period of food scarcity. That period rarely comes in our society today and the result is obesity, with all of its attendant comorbidities.
We are interested in the functions of PASK, an evolutionarily conserved serine/threonine kinase, in coupling nutrient status with metabolic state, energy storage and growth. 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 .
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 .
Jonathan G. Van Vranken1, Sara M. Nowinski1, Katie J. Clowers4, Mi-Young Jeong1,2,Yeyun Ouyang1, Jordan A. Berg1, Jeremy P. Gygi4, Steven P. Gygi4, Dennis R. Winge1,2, and Jared Rutter1,3,5* (In press). ACP acylation is an acetyl-CoA-dependent modification required for electron transport chain assembly.
Zurita Rendón O, Fredrickson EK, Howard CJ, Van Vranken J, Fogarty S, Tolley ND, Kalia R, Osuna BA, Shen PS, Hill CP, Frost A, Rutter J. Vms1p is a release factor for the ribosome-associated quality control complex. Nat Commun. 2018 Jun 6;9(1):2197. doi: 10.1038/s41467-018-04564-3. PMID: 29875445
Nielson JR, Fredrickson EK, Waller TC, Rendón OZ, Schubert HL, Lin Z, Hill CP, Rutter J. Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria. Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022. PMID: 29149595
Schell, J.C., D.R. Wisidigama, C. Bensard, H. Zhao, P. Wei, J. Tanner, A. Flores, J. Mohlman, L. Sorensen, C. Earl, K.A. Olson, R. Miao, T.C. Waller, D. Delker, P. Kanth, L. Jiang, R.J. Deberardinis, M. Bronner, D.Y. Li, J.E. Cox, H.R. Christofk, W.E. Lowry, C.S. Thummel, and J. Rutter. Control of Intestinal Stem Cell Function and Proliferation by Mitochondrial Pyruvate Metabolism. Nat Cell Biol, 2017. In Press.
- Olson, K.A., J.C. Schell, and J. Rutter, Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies. Trends Biochem Sci, 2016. 41(3): 219-30.
- Orsak, T., T.L. Smith, D. Eckert, J.E. Lindsley, C.R. Borges, and J. Rutter, Revealing the allosterome: systematic identification of metabolite-protein interactions. Biochemistry, 2012. 51(1): p. 225-32.
- Pagliarini, D.J., S.E. Calvo, B. Chang, S.A. Sheth, S.B. Vafai, S.E. Ong, G.A. Walford, C. Sugiana, A. Boneh, W.K. Chen, D.E. Hill, M. Vidal, J.G. Evans, D.R. Thorburn, S.A. Carr, and V.K. Mootha, A mitochondrial protein compendium elucidates complex I disease biology. Cell, 2008. 134(1): p. 112-23.
- Elstner, M., C. Andreoli, U. Ahting, I. Tetko, T. Klopstock, T. Meitinger, and H. Prokisch, MitoP2: an integrative tool for the analysis of the mitochondrial proteome. Mol Biotechnol, 2008. 40(3): p. 306-15.
- Andreoli, C., H. Prokisch, K. Hortnagel, J.C. Mueller, M. Munsterkotter, C. Scharfe, and T. Meitinger, MitoP2, an integrated database on mitochondrial proteins in yeast and man. Nucleic Acids Res, 2004. 32(Database issue): p. D459-62.
- Hao, H.X., O. Khalimonchuk, M. Schraders, N. Dephoure, J.P. Bayley, H. Kunst, P. Devilee, C.W. Cremers, J.D. Schiffman, B.G. Bentz, S.P. Gygi, D.R. Winge, H. Kremer, and J. Rutter, SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science, 2009. 325(5944): p. 1139-42.
- Hao, H.X. and J. Rutter, Revealing human disease genes through analysis of the yeast mitochondrial proteome. Cell Cycle, 2009. 8(24): p. 4007-8.
- Heo, J.M., N. Livnat-Levanon, E.B. Taylor, K.T. Jones, N. Dephoure, J. Ring, J. Xie, J.L. Brodsky, F. Madeo, S.P. Gygi, K. Ashrafi, M.H. Glickman, and J. Rutter, A stress-responsive system for mitochondrial protein degradation. Mol Cell, 2010. 40(3): p. 465-80.
- Taylor, E.B. and J. Rutter, Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans, 2011. 39(5): p. 1509-13.
- Chen, Y.C., E.B. Taylor, N. Dephoure, J.M. Heo, A. Tonhato, I. Papandreou, N. Nath, N.C. Denko, S.P. Gygi, and J. Rutter, Identification of a protein mediating respiratory supercomplex stability. Cell Metab, 2012. 15(3): p. 348-60.
- Chen, Y.C., G.K. Umanah, N. Dephoure, S.A. Andrabi, S.P. Gygi, T.M. Dawson, V.L. Dawson, and J. Rutter, Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins.EMBO J, 2014. 33(14): p. 1548-64.
- Van Vranken, J.G., D.K. Bricker, N. Dephoure, S.P. Gygi, J.E. Cox, C.S. Thummel, and R. J., SDHAF4 promotes mitochondrial succinate dehydrogenase activity and prevents neurodegeneration. Cell Metab, 2014. 20(2): p. 241-52.
- Bricker, D.K., E.B. Taylor, J.C. Schell, T. Orsak, A. Boutron, Y.C. Chen, J.E. Cox, C.M. Cardon, J.G. Van Vranken, N. Dephoure, C. Redin, S. Boudina, S.P. Gygi, M. Brivet, C.S. Thummel, and J. Rutter, A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science, 2012. 337(6090): p. 96-100.
- Schell, J.C., K.A. Olson, L. Jiang, A.J. Hawkins, J.G. Van Vranken, J. Xie, R.A. Egnatchik, E.G. Earl, R.J. Deberardinis, and J. Rutter, A Role for the Mitochondrial Pyruvate Carrier as a Repressor of the Warburg Effect and Colon Cancer Cell Growth. Mol Cell, 2014. 56: p. 1-14.
- Hao, H.X., C.M. Cardon, W. Swiatek, R.C. Cooksey, T.L. Smith, J. Wilde, S. Boudina, E.D. Abel, D.A. McClain, and J. Rutter, PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci U S A, 2007. 104(39): p. 15466-71.
- Wu, X., D. Romero, W. Swiatek, I. Dorweiler, C.K. Kikani, H. Sabic, B.S. Zweifel, J. Mckearn, J.T. Blitzer, G.A. Nickols, and R. J., PAS Kinase Drives Lipogenesis Through SREBP-1 Maturation. Cell Reports, 2014. 8(1): p. 242-55.