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Jared Rutter

Professor of Biochemistry and
Adjunct Professor of Nutrition and Integrative Physiology

Rutter Photo

HHMI Investigator

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

 Molecular Biology Program

Biological Chemistry Program

Cancer metabolism, Diabetes & obesity, Metabolic signaling

Research

The Rutter laboratory is interested in discovering new ways to understand metabolism and how it integrates with cell behavior. We are currently exploring two central areas. 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 are leveraging this knowledge to explore the connection between metabolism and cellular behaviors. Specifically, we want to determine how alterations in distinct metabolic pathways can impact cell fate decisions both in discrete stem cell niches as well as in human diseases such as cancer and heart failure. To facilitate this undertaking we are developing several experimental and computational platforms for the identification and characterization of novel features of metabolism.

  1. Functionalizing 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. 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 towards this goal, we used the yeast, Saccharomyces cerevisiae, as a model system in which to genetically and biochemically characterize a number of evolutionarily conserved but understudied mitochondrial protein families. A subset of these proteins, all of which had no previously described function, were analyzed by a combination of biochemical, metabolomic, and cell biological approaches to reveal novel roles in mitochondrial biology, some of which are described below:

Mitochondrial Pyruvate Carrier: The fate of pyruvate is one of the most important metabolic decisions made by eukaryotic cells. Most normal, differentiated mammalian cells partition pyruvate primarily toward transport into mitochondria where it is oxidized for efficient ATP production. The partitioning of pyruvate in stem cells, cancer cells, and failing hearts, however, is different—away from mitochondrial oxidation. Our ability to understand the molecular basis for these metabolic distinctions has been hampered by the surprising fact that the mitochondrial pyruvate transporter had not been identified until now. We discovered a protein complex consisting of Mpc1 and Mpc2 that constitutes the major mitochondrial pyruvate transporter in yeast, Drosophila, and humans. Empowered by this discovery, we found that three families with children suffering from lactic acidosis and hyperpyruvatemia had causal mutations in MPC1.

MitoFAS: We demonstrated that the mitochondrial acyl carrier protein (ACP), which has a well-known role in mitochondrial fatty acid synthesis (mitoFAS), plays an unexpected and evolutionarily conserved role in FeS biogenesis. Subsequent work, highlighted the role of mitoFAS as a nutrient-sensitive pathway that provides an elegant mechanism whereby acetyl-CoA regulates its own consumption via coordination of lipoic acid synthesis and tricarboxylic acid (TCA) cycle activity, iron-sulfur (FeS) cluster biogenesis, assembly of oxidative phosphorylation complexes, and mitochondrial translation.

Mitochondrial Protein Quality Control: Msp1/ATAD1 is a AAA-ATPase protein that we found to reside on the mitochondrial outer membrane. Through a combination of genetics and biochemistry, we showed that it extracts proteins that mis-localize to the mitochondrial outer membrane, which we observed as a surprisingly common phenomenon. We demonstrated this function for the protein family in yeast, human cells, and knockout mice. We found that Vms1 is required for the stress-responsive mitochondrial recruitment of Cdc48/VCP/p97 and Npl4, which play a role in protein extraction and degradation. Further studies led to the conclusion that Vms1 is a critical component of a previously unknown system for mitochondrial protein quality control, eliminating damaged or misfolded proteins that promote progressive mitochondrial dysfunction.

Regulation of Electron Transport Chain Assembly: We found that both Sdh5 and Sdh8 are required for the assembly of the succinate dehydrogenase complex (Complex II) of the electron transport chain. As a result of these mechanistic functional studies, we were able to discover that familial mutations in human SDH5 (SDHAF2) cause a paraganglioma tumor syndrome. We also discovered a role for Rcf1 in the normal assembly of respiratory supercomplexes in yeast and mammals. Deletion of the RCF1 gene caused impaired respiration and elevated mitochondrial oxidative stress and damage.

  1. The connection between metabolism and cellular behaviors

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. These discoveries support the notion that the metabolic program of stem cells is not a byproduct of their environments or a passive feature of their cell biology, but rather a driving force that influences their fate and function.

Metabolic underpinnings of cancer and stem cells: Our discovery of the Mitochondrial Pyruvate Carrier (MPC) has led to the initiation of a significant effort in the lab to understand the fundamental metabolic underpinnings of cancer and stem cells. Modulation of pyruvate metabolism via chemical or genetic manipulation of the MPC has profound effects on intestinal stem cell function and proliferation as well as on cancer metabolism, supporting the idea that metabolism is not merely a by-product but rather an intrinsic driving force of cell fate. We are currently extending these studies using mouse models of human diseases including colon cancer and heart failure.

MIDAS: Small molecule allostery modifies protein function but is not easily discoverable. We have developed an experimental platform - mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) - that enables the identification of physiologically relevant, low-affinity metabolite-protein interactions using unmodified proteins and complex mixtures of unmodified metabolites. Our latest iteration of MIDAS enables high-throughput identification of the allesterome of purified proteins to uncover novel aspects of biology.

PASK: PAS domain containing protein kinase (Pask) is an evolutionarily conserved, nutrient-sensing serine/threonine protein kinase implicated in energy homeostasis and metabolic regulation across eukaryotic species. We recently described an unexpected role for Pask in regulating the differentiation of stem and progenitor cells into neuronal, adipocytes, and myocytes lineages. Subsequent work has shown that Pask is an interacting partner and a direct substrate of mTORC1, and that is a necessary mediator of the alterations in epigenetic markers that drive muscle cell differentiation in response to nutrient and hormonal signals.

References

  1. Kikani CK, Wu X, Fogarty S, Kang SAW, Dephoure N, Gygi SP, Sabatini DM, RutterJ. Activation of PASK by mTORC1 is required for the onset of the terminaldifferentiation program. Proc Natl Acad Sci U S A. 2019 May21;116(21):10382-10391. doi: 10.1073/pnas.1804013116. Epub 2019 May 9. PubMed PMID: 31072927; PubMed Central PMCID: PMC6534978.
  2. Nowinski SM, Van Vranken JG, Dove KK, Rutter J. Impact of Mitochondrial Fatty Acid Synthesis on Mitochondrial Biogenesis. Curr Biol. 2018 Oct
    22;28(20):R1212-R1219. doi: 10.1016/j.cub.2018.08.022. Review. PubMed PMID: 30352195; PubMed Central PMCID: PMC6258005.
  3. Van Vranken JG, Nowinski SM, Clowers KJ, Jeong MY, Ouyang Y, Berg JA, Gygi JP,Gygi SP, Winge DR, Rutter J. ACP Acylation Is an Acetyl-CoA-DependentModification Required for Electron Transport Chain Assembly. Mol Cell. 2018 Aug16;71(4):567-580.e4. doi: 10.1016/j.molcel.2018.06.039. PubMed PMID: 30118679; PubMed Central PMCID: PMC6104058.
  4. Sips PY, Shi X, Musso G, Nath AK, Zhao Y, Nielson J, Morningstar J, Kelly AE, Mikell B, Buys E, Bebarta V, Rutter J, Davisson VJ, Mahon S, Brenner M, Boss GR, Peterson RT, Gerszten RE, MacRae CA. Identification of specific metabolicpathways as druggable targets regulating the sensitivity to cyanide poisoning.PLoS One. 2018 Jun 7;13(6):e0193889. doi: 10.1371/journal.pone.0193889.eCollection 2018. PubMed PMID: 29879736; PubMed Central PMCID: PMC5991913.
  5. Zurita Rendón O, Fredrickson EK, Howard CJ, Van Vranken J, Fogarty S, TolleyND, Kalia R, Osuna BA, Shen PS, Hill CP, Frost A, Rutter J. Vms1p is a releasefactor for the ribosome-associated quality control complex. Nat Commun. 2018 Jun 6;9(1):2197. doi: 10.1038/s41467-018-04564-3. PubMed PMID: 29875445; PubMed Central PMCID: PMC5989216.
  6. Nielson JR, Rutter JP. Lipid-mediated signals that regulate mitochondrialbiology. J Biol Chem. 2018 May 18;293(20):7517-7521. doi: 10.1074/jbc.R117.001655. Epub 2018 Jan 18. Review. PubMed PMID: 29348169; PubMed  Central PMCID: PMC5961036.
  7. 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. PubMed PMID: 29149595; PubMed Central PMCID: PMC5837041.
  8. Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS, Olson KA, Miao R, Waller TC, Delker D, Kanth P, Jiang L, DeBerardinis RJ, Bronner MP, Li DY, Cox JE, Christofk HR, Lowry WE, Thummel CS, Rutter J. Control of intestinal stem cell function and proliferation  by mitochondrial pyruvate metabolism. Nat Cell Biol. 2017 Sep;19(9):1027-1036. doi: 10.1038/ncb3593. Epub 2017 Aug 14. PubMed PMID: 28812582; PubMed Central PMCID: PMC6137334.
  9. Diakos NA, Navankasattusas S, Abel ED, Rutter J, McCreath L, Ferrin P,McKellar SH, Miller DV, Park SY, Richardson RS, Deberardinis R, Cox JE, Kfoury AG, Selzman CH, Stehlik J, Fang JC, Li DY, Drakos SG. Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning. JACC Basic Transl Sci. 2016 Oct;1(6):432-444. doi: 10.1016/j.jacbts.2016.06.009. Epub 2016 Oct 31. PubMed PMID: 28497127; PubMed Central PMCID: PMC5422992.
  10. Kikani CK, Wu X, Paul L, Sabic H, Shen Z, Shakya A, Keefe A, Villanueva C, Kardon G, Graves B, Tantin D, Rutter J. Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis. Elife. 2016 Sep 23;5. pii: e17985. doi: 10.7554/eLife.17985. PubMed PMID: 27661449; PubMed Central PMCID: PMC5035144.
  11. Van Vranken JG, Jeong MY, Wei P, Chen YC, Gygi SP, Winge DR, Rutter J. The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis. Elife. 2016 Aug 19;5. pii: e17828. doi: 10.7554/eLife.17828. PubMed PMID: 27540631; PubMed Central PMCID: PMC4991935.
  12. Olson KA, Schell JC, Rutter J. Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies. Trends Biochem Sci. 2016 Mar;41(3):219-230. doi: 10.1016/j.tibs.2016.01.002. Epub 2016 Feb 10. Review. PubMed PMID: 26873641; PubMed Central PMCID: PMC4783264.
  13. Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, Earl EG, DeBerardinis RJ, Rutter J. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 2014 Nov 6;56(3):400-13. doi: 10.1016/j.molcel.2014.09.026. Epub 2014 Oct 21. PubMed PMID: 25458841; PubMed Central PMCID: PMC4268416.
  14. Wu X, Romero D, Swiatek WI, Dorweiler I, Kikani CK, Sabic H, Zweifel BS, McKearn J, Blitzer JT, Nickols GA, Rutter J. PAS kinase drives lipogenesis through SREBP-1 maturation. Cell Rep. 2014 Jul 10;8(1):242-55. doi: 10.1016/j.celrep.2014.06.006. Epub 2014 Jul 4. PubMed PMID: 25001282; PubMed Central PMCID: PMC4112965.
  15. Van Vranken JG, Bricker DK, Dephoure N, Gygi SP, Cox JE, Thummel CS, Rutter J. SDHAF4 promotes mitochondrial succinate dehydrogenase activity and prevents neurodegeneration. Cell Metab. 2014 Aug 5;20(2):241-52. doi: 10.1016/j.cmet.2014.05.012. Epub 2014 Jun 19. PubMed PMID: 24954416; PubMed Central PMCID: PMC4126880.
  16. Chen YC, Umanah GK, Dephoure N, Andrabi SA, Gygi SP, Dawson TM, Dawson VL, Rutter J. Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J. 2014 Jul 17;33(14):1548-64. doi: 10.15252/embj.201487943. Epub 2014 May 19. PubMed PMID: 24843043; PubMed Central PMCID: PMC4198051.
  17. Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 2012 Jul 6;337(6090):96-100. doi: 10.1126/science.1218099. Epub 2012 May 24. PubMed PMID: 22628558; PubMed Central  PMCID: PMC3690818.
  18. Heo JM, Livnat-Levanon N, Taylor EB, Jones KT, Dephoure N, Ring J, Xie J, Brodsky JL, Madeo F, Gygi SP, Ashrafi K, Glickman MH, Rutter J. A
    stress-responsive system for mitochondrial protein degradation. Mol Cell. 2010 Nov 12;40(3):465-80. doi: 10.1016/j.molcel.2010.10.021. PubMed PMID: 21070972; PubMed Central PMCID: PMC2998070.
  19. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee  P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009 Aug 28;325(5944):1139-42. doi: 10.1126/science.1175689. Epub 2009 Jul 23. PubMed PMID: 19628817; PubMed Central  PMCID: PMC3881419.
  20. Hao HX, Cardon CM, Swiatek W, Cooksey RC, Smith TL, Wilde J, Boudina S, Abel  ED, McClain DA, Rutter J. PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15466-71. Epub 2007 Sep 18. PubMed PMID: 17878307; PubMed Central PMCID: PMC2000499.

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Last Updated: 7/16/19