Research in the Culotta lab focuses on the role of metal ions and oxygen radicals in biology and disease. Metal ions such as copper, iron and manganese are not only trace nutrients but can be quite toxic. One mechanism of toxicity is through generation of reactive oxygen species (ROS) that have been implicated in numerous human disorders from neurodegeneration to cancer to aging. Through molecular genetic approaches and high through-put genetic screens in yeast, we have identified a number genes and pathways that are involved in transition metal and reactive oxygen metabolism. Virtually all are well conserved throughout eukaryotes including humans. Our laboratory uses a combination of yeast, C. elegans and cell culture systems at the crossroads of bioinorganic chemistry, cell biology and molecular genetics.

Environmental Health Sciences, copper, manganese, iron, ROS, metal toxicity, ALS, SOD

Leitch JM, Yick PJ, Culotta VL The right to choose: Multiple pathways for activating Cu/Zn superoxide dismutase. J Biol Chem. 2009 284(37):24679-2468

Naranuntarat A, Jensen LT, Pazicni S, Penner-Hahn JE, Culotta VC The interaction of mitochondrial iron with manganese superoxide dismutase. J Biol Chem. 2009 284(34):22633-40

Leitch JM, Jensen LT, Bouldin SD, Outten CE, Hart PJ, Culotta VC Activation of Cu,Zn-Superoxide Dismutase in the Absence of Oxygen and the Copper Chaperone CCS J Biol Chem. 2009 Aug 14;284(33):21863-71

Laran T. Jensen, Mark C. Carroll, Matthew D. Hall, Christopher J. Harvey, Sara E. Beese, and Valeria C. Culotta Down-Regulation of a Manganese Transporter in the Face of Metal Toxicity. Mol. Biol. Cell 2009 Jun;20(12):2810-9

Reddi AR, Jensen LT, Naranuntarat A, Rosenfeld L, Leung E, Shah R, Culotta VC. The overlapping roles of manganese and Cu/Zn SOD in oxidative stress protection. Free Radic Biol Med. 2009 Jan 15;46(2):154-62

Kirby K, Jensen LT, Binnington J, Hilliker AJ, Ulloa J, Culotta VC, Phillips JP. Instability of superoxide dismutase 1 of Drosophila in mutants deficient for its cognate copper chaperone. J Biol Chem. 2008 Dec 19;283(51):35393-401

Proescher JB, Son M, Elliott JL, Culotta VC. Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS. Hum Mol Genet. 2008 Jun 15;17(12):1728-37

Activation of superoxide dismutases: putting the metal to the pedal. Culotta VC, Yang M, O'Halloran TV. Biochim Biophys Acta. 2006 Jul;1763(7):747-58

Yang M, Cobine PA, Molik S, Naranuntarat A, Lill R, Winge DR, Culotta VC. The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2. EMBO J. 2006 Apr 19;25(8):1775-8

Carroll MC, Outten CE, Proescher JB, Rosenfeld L, Watson WH, Whitson LJ, Hart PJ, Jensen LT, Cizewski Culotta V. The effects of glutaredoxin and copper activation pathways on the disulfide and stability of Cu,Zn superoxide dismutase. J Biol Chem. 2006 Sep 29;281(39):28648-56

Jensen LT, Culotta VC. Activation of CuZn superoxide dismutases from Caenorhabditis elegans does not require the copper chaperone CCS. J Biol Chem. 2005 Dec 16;280(50):41373-9.

Luk E, Yang M, Jensen LT, Bourbonnais Y, Culotta VC. Manganese activation of superoxide dismutase 2 in the mitochondria of Saccharomyces cerevisiae. J Biol Chem. 2005 Jun 17;280(24):22715-20.

Carroll MC, Girouard JB, Ulloa JL, Subramaniam JR, Wong PC, Valentine JS, Culotta VC. Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5964-9

Jensen LT, Sanchez RJ, Srinivasan C, Valentine JS, Culotta VC. Mutations in Saccharomyces cerevisiae iron-sulfur cluster assembly genes and oxidative stress relevant to Cu,Zn superoxide dismutase. J Biol Chem. 2004 Jul 16;279(29):29938-43

Outten CE, Culotta VC.Alternative start sites in the Saccharomyces cerevisiae GLR1 gene are responsible for mitochondrial and cytosolic isoforms of glutathione reductase. J Biol Chem. 2004 Feb 27;279(9):7785-91

Jensen LT, Ajua-Alemanji M, Culotta VC. The Saccharomyces cerevisiae high affinity phosphate transporter encoded by PHO84 also functions in manganese homeostasis. J Biol Chem. 2003 Oct 24;278(43):42036-40

Luk E, Carroll M, Baker M, Culotta VC. Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1, a member of the mitochondrial carrier family. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10353-7

Field LS, Furukawa Y, O'Halloran TV, Culotta VC. Factors controlling the uptake of yeast copper/zinc superoxide dismutase into mitochondria. J Biol Chem. 2003 Jul 25;278(30):28052-9

Outten CE, Culotta VC.A novel NADH kinase is the mitochondrial source of NADPH in Saccharomyces cerevisiae. EMBO J. 2003 May 1;22(9):2015-24

Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002 Jul 18;418(6895):344-8

Luk, EE and Culotta, VC. Manganese superoxide dismutase in S. cerevisiae acquires its metal co-factor through a pathway involving the Nramp metal transporter, Smf2p. J Biol Chem. 2001 Oct 15

Sturtz LA, Diekert K, Jensen LT, Lill R, Culotta VC. A fraction of yeast cu,zn-superoxide dismutase and its metallochaperone, ccs, localize to the intermembrane space of mitochondria. a physiological role for sod1 in guarding against mitochondrial oxidative damage. J Biol Chem. 2001 276:38084-9

Portnoy ME, Liu XF, Culotta VC. Saccharomyces cerevisiae expresses three functionally distinct homologues of the nramp family of metal transporters. Mol Cell Biol. 2000 20:7893-902

O'Halloran, T.V. and Culotta, V.C. 2000. Metallochaperones: an intracellular shuttle service for metal irons. J. Biol. Chem., 275:25057-60.

Rae, T.D., Schmidt, P.J., Pufhal, R.A., Culotta, V.C. and O'Halloran, T.V. 1999. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science, 284:805-808.

Lamb AL, Wernimont AK, Pufahl RA, Culotta VC, O'Halloran TV, Rosenzweig AC. Crystal structure of the copper chaperone for superoxide dismutase. Nat Struct Biol. 1999 Aug;6(8):724-9

3. Pufahl, R., Singer, C., Peariso, K. L., Lin, S. J., Schmidt, P., Fahrni, C., Culotta, V. C., Penner-Hahn, J. E. and O'Halloran, T. V. Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science. 278:853-856, 1997