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Training Grant-
Biology of Aging

David Pagliarini

David J. Pagliarini

Ph.D., University of California- San Diego
Associate Professor, Department of Biochemistry
Lead Investigator & Nielsen Chair of Metabolism, Morgridge Institute for Research

Mitochondrial Energy Metabolism in Aging and Age-Related Diseases

Mitochondrial energy metabolism figures prominently in central aging paradigms. On one hand, increased expression of mitochondrial electron transport chain (ETC) machinery is a hallmark of caloric restriction-mediated lifespan extension. On the other hand, mutation or reduced function of particular nuclear genes encoding ETC components leads to prolonged lifespan in yeast, C. elegans, Drosophila, and mice. Moreover, mitochondrial energy metabolism is implicated in a wide range of age-related human pathologies, including type 2 diabetes, metabolic syndrome, obesity, Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS, cardiomyopathy, and various cancers. Indeed, it has even been speculated that all age-related metabolic and degenerative disorders might have their origin in mitochondrial functional decline and mtDNA damage.

Our laboratory blends large-scale mass spectrometry-based proteomics and metabolomics approaches with focused biochemistry and cell biology to explore metabolic and signaling function of mitochondria and how these processes relate to aging and age-related diseases.

Representative Publications
Lapointe, C. P., Stefely, J. A., Jochem, A., Hutchins, P. D., Wilson, G. M., Kwiecien, N. W., Coon, J. J., Wickens, M., & Pagliarini, D. J. (2018). Multi-omics reveal specific targets of the RNA-binding protein puf3p and its orchestration of mitochondrial biogenesis. Cell Systems, 6(1), 125-135.e126.
View publication via DOI: DOI:10.1016/j.cels.2017.11.012

Reidenbach, A. G., Kemmerer, Z. A., Aydin, D., Jochem, A., McDevitt, M. T., Hutchins, P. D., ... & Pagliarini, D. J. (2018). Conserved lipid and small-molecule modulation of COQ8 reveals regulation of the ancient kinase-like UbiB family. Cell Chemical Biology, 25(2), 154-165.e111.
View publication via DOI: DOI:10.1016/j.chembiol.2017.11.001

Wisnovsky, S., Sack, T., Pagliarini, D. J., Laposa, R. R., & Kelley, S. O. (2018). DNA polymerase theta increases mutational rates in mitochondrial DNA. ACS Chemical Biology. Advance online publication.
View publication via DOI: DOI:10.1021/acschembio.8b00072

Guo, X., Niemi, N. M., Hutchins, P. D., Condon, S. G. F., Jochem, A., Ulbrich, A., Higbee, A. J., Russell, J. D., Senes, A., Coon, J. J., & Pagliarini, D. J. (2017). Ptc7p dephosphorylates select mitochondrial proteins to enhance metabolic function. Cell Reports, 18(2), 307-313.
View publication via DOI: DOI:10.1016/j.celrep.2016.12.049

Chung, J., Wittig, J. G., Ghamari, A., Maeda, M., Dailey, T. A., Bergonia, H., ... Pagliarini, D. J., Dailey, H. A., & Paw, B. H. (2017). Erythropoietin signaling regulates heme biosynthesis. eLife, 6, e24767.
View publication via DOI: DOI:10.7554/eLife.24767

Guo, X., Niemi, N. M., Coon, J. J., & Pagliarini, D. J. (2017). Integrative proteomics and biochemical analyses define Ptc6p as the Saccharomyces cerevisiae pyruvate dehydrogenase phosphatase. Journal of Biological Chemistry, 292(28), 11751-11759.
View publication via DOI: DOI:10.1074/jbc.M117.787341

Guo, X., Niemi, N. M., Hutchins, P. D., Condon, S. G., Jochem, A., Ulbrich, A., Higbee, A. J., Russell, J. D., Senes, A., Coon, J. J., & Pagliarini, D. J. (2017). Ptc7p dephosphorylates select mitochondrial proteins to enhance metabolic function. Cell Reports, 18(2), 307-313.
View publication via DOI: DOI:10.1016/j.celrep.2016.12.049

Stefely, J. A., & Pagliarini, D. J. (2017). Biochemistry of mitochondrial coenzyme Q biosynthesis. Trends in Biochemical Sciences, 42(10), 824-843.
View publication via DOI: DOI:10.1016/j.tibs.2017.06.008

Veling, M. T., Reidenbach, A. G., Freiberger, E. C., Kwiecien, N. W., Hutchins, P. D., Drahnak, M. J., & ... Pagliarini, D. J. (2017). Multi-omic mitoprotease profiling defines a role for Oct1p in coenzyme Q production. Molecular Cell, 68(5), 970-977.e911.
View publication via DOI: DOI:10.1016/j.molcel.2017.11.023

Stefely, J. A., Kwiecien, N. W., Freiberger, E., Richards, A. L., Jochem, A., Rush, M. J. P. , Ulbrich, A., Robinson, K. P., Hutchins, P. D., Veling, M. T., Guo, X., Kemmerer, Z. A., Connors, K. J., Trujillo, E. A., ... Pagliarini, D. J., & Coon, J. J (2016). Mitochondrial protein functions elucidated by global mass spectrometry profiling. Nature Biotechnology, 34(11), 1191-1197.
View publication via DOI: DOI:10.1038/nbt.3683

Rensvold, J. W., Krautkramer, K. A., Dowell, J. A., Denu, J. M., & Pagliarini, D. J. (2016). Iron deprivation induces transcriptional regulation of mitochondrial biogenesis. Molecular Cell, 63(4), 621-632.
View publication via DOI: DOI:10.1016/j.molcel.2016.06.033

Stefely, J. A., Licitra, F., Laredj, L., Reidenbach, A. G., Kemmerer, A. Z., Grangeray, A., ... Pagliarini, D. J.. (2016). Cerebellar ataxia and coenzyme Q deficiency through loss of unorthodox kinase activity. Molecular Cell, 63(4), 608-620.
View publication via DOI: DOI:10.1016/j.molcel.2016.06.030

Pagliarini, D. J. (2016). Transomics: Mitochondrial systems analyses get supercomplex. Cell Metabolism, 24(1), 13-14.
View publication via DOI: DOI:10.1016/j.cmet.2016.06.018

Horton, J. L., Martin, O. J., Lai, L., Riley, N. M., Richards, A., Vega, R. G., Leone, T. C., Pagliarini, D. J., Coon, J. J., Muoio, D., Bedi, Jr. D. K., Margulies, K. B., & Kelly, D. P. (2016). Mitochondrial protein hyperacetylation in the failing heart. JCI Insight, 1(2), e84897.
View publication via DOI: DOI:10.1172/jci.insight.84897

Overmyer, K.A., Evans, C.R., Qi, N.R., Minogue, C.V., Chermside-Scaboo, C.J., Kock, L.G., Britton, S.L., Pagliarini, D.J., Coon, J.J., & Burant, C.F. (2015). Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. Cell Metabolism, 21(3), 468-478.
View publication via DOI: DOI:10.1016/j.cmet.2015.02.007

Stefely, J.A., Reidenbach, A.G., Ulbrich, A., Oruganty, K., Floyd, B.J., Jochem, A., ... C.A. & Pagliarini, D.J. (2015). Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable ubiquinone biosynthesis. Molecular Cell, 57(1), 83-94.
View publication via DOI: DOI:10.1016/j.molcel.2014.11.002

Tagliabracci, V.S., Wiley, S.E., Guo, X., Kinch, L.N., Durrant, E., Wen, J., Xiao, J., Cui, J., Nguyen, K.B., Engel, J.L., Coon, J.J., Grishin, N., Pinna, L.A., Pagliarini, D.J., & Dixon, J.E. (2015). A single kinase generates the majority of the secreted phosphoproteome. Cell, 161(7), 1619-32.
View publication via DOI: DOI:10.1016/j.cell.2015.05.028

Minogue, C.E., Hebert, A.S., Rensvold, J.W., Westphall, M.S., Pagliarini, D.J., & Coon, J.J. (2015). Multiplexed quantification for data-independent acquisition. Analytical Chemistry, 87(5), 2570-5.
View publication via DOI: DOI:10.1021/ac503593d

Lohman, D.C., Forouhar, F., Beebe, E.T., Stefely, M.S., Minogue, C.E., Ulbrich, A.,... & Pagliarini, D.J. (2014). Mitochondrial COQ9 is a lipid binding protein that associates with COQ7 to enable coenzyme Q biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 111(44), E4697-705.
View publication via DOI: DOI:10.1073/pnas.1413128111

Khadria, A.S., Mueller, B.K., Stefely, J.A., Tan, C.H., Pagliarini, D.J., & Senes, A. (2014). A Gly-zipper motif mediates homo-dimerization of the transmembrane domain of the mitochondrial kinase ADCK3. Journal of the American Chemical Society, 136(40), 14068-77.
View publication via DOI: DOI:10.1021/ja505017f

Vincent, C.E., Rensvold, J.W., Westphall, M.S., Pagliarini, D.J., & Coon, J.J. (2013). Automated Gas-Phase Purification for Accurate, Multiplexed Quantification on a Stand-Alone Ion-Trap Mass Spectrometer. Analytical Chemistry, 85(4), 2079-2086.
View publication via DOI: DOI:10.1021/ac302156t

Hebert, A.S., Dittenhafer-Reed, K.E., Yu, W., Bailey, D.J., Selen, E.S., Boersma, M.D., ... Pagliarini, D.J., Prolla, T.A., ... Coon, J.J. (2013). Calorie Restriction and SIRT3 Trigger Global Reprogramming of the Mitochondrial Protein Acetylome. Molecular Cell, 49(1), 186-99.
View publication via DOI: DOI:10.1016/j.molcel.2012.10.024

Rensvold, J.W., Ong, S.E., Jeevananthan, A., Carr, S.A., Mootha, V.K. & Pagliarini, D.J. (2013). Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis. Cell Reports, 3(1), 237-245.
View publication via DOI: DOI:10.1016/j.celrep.2012.11.029

Pagliarini, D. J., & Rutter, J. (2013). Hallmarks of a new era in mitochondrial biochemistry. Genes & Development, 27, 2615-2627.
View publication via DOI: DOI:10.1101/gad.229724.113

Still, A. J., Floyd, B. J., Hebert, A. S., Bingman, C. A., Carson, J. J., Gunderson, D. R., . . . Pagliarini, D. J. (2013). Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. Journal of Biological Chemistry. Advance online publication.
View publication via DOI: DOI:10.1074/jbc.M113.483396

McAlister, G., Russell, J., Rumachik, N., Hebert, A., Syka, J., Geer, L., Westphall, M., Pagliarini, D.J., & Coon, J.J. (2012). Analysis of the acidic proteome with negative electron-transfer dissociation mass spectrometry. Analytical Chemistry, 84(6), 2875-82.
View publication via DOI: DOI:10.1021/ac203430u

Eletsky, A., Jeong, M.Y., Kim, H., Lee, H.W., Xiao, R., Pagliarini, D.J., ... Szyperski, T. (2012). Solution NMR Structure of Yeast Succinate Dehydrogenase Flavination Factor Sdh5 Reveals a Putative Sdh1 Binding Site. Biochemistry, 51(43), 8475-7.
View publication via DOI: DOI:10.1021/bi301171u

Shenton, D.D., Joseph, J.D., Zhang, J., Pagliarini, D.J., Kim, Y., Lu, D., ... Casey, P.J. (2010). Pharmacological targeting of the mitochondrial phosphatase PTPMT1. The Journal of Pharmacology and Experimental Therapeutics, 332(2), 584-592.
View publication via DOI: DOI:10.1124/jpet.109.163329

Calvo, S.E., Pagliarini, D.J., & Mootha, V.K. (2009). Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proceedings of the National Academy of Sciences USA, 106, 7507-7512.
View publication via DOI: DOI:10.1073/pnas.0810916106

Rardin, M.J., Wiley, S.E., Murphy, A.N., Pagliarini, D.J., & Dixon, J.E. (2008). Dual specific phosphatases 18 and 21 target to opposing sides of the mitochondrial inner membrane. Journal of Biological Chemistry, 283(22), 15440-15450.
View publication via DOI: DOI:10.1074/jbc.M709547200

Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E, ... Mootha, V.K. (2008). A mitochondrial protein compendium elucidates complex I disease biology. Cell, 134(1), 112-123.
View publication via DOI: DOI:10.1016/j.cell.2008.06.016

Sugiana, C., Pagliarini, D.J., McKenzie, M., Kirby, D.M., Salemi, R., Dahl, H.H.M., ...Thorburn, D.R. (2008). Mutation of C20orf7 disrupts Complex I assembly and causes lethal infantile mitochondrial disease. American Journal of Human Genetics, 83(4), 468-478.
View publication via DOI: DOI:10.1016/j.ajhg.2008.09.009

Pagliarini, D.J., & Dixon, J.E. (2006). Mitochondrial modulation: Reversible phosphorylation takes center stage? Trends in Biochemical Sciences, 31(1), 26-34.
View publication via DOI: DOI:10.1016/j.tibs.2005.11.005

Pagliarini, D.J., Wiley, S.E., Kimple, M.E., Dixon, J.R., Kelly, P., Casey, P.J., ...Dixon, J.E. (2005). Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic β cells. Molecular Cell, 19(2), 197-207.
View publication via DOI: DOI:10.1016/j.molcel.2005.06.008

Pagliarini, D.J., Worby, C.A., & Dixon, J.E. (2004). A PTEN-like phosphatase with a novel substrate specificity. Journal of Biological Chemistry, 279, 38590-38596.
View publication via DOI: DOI:10.1074/jbc.M404959200

Merlot, S., Meili, R., Pagliarini, D.J., Maehama, T., Dixon, E., & Firtel, R.A. (2003). A PTEN-related 5-phosphatidylinositol phosphatase localized in the golgi. Journal of Biological Chemistry, 278, 39866-39873.
View publication via DOI: DOI:10.1074/jbc.M306318200

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