Cecilia Giulivi

image of Cecilia Giulivi

Professor, Director of the Redox Biology Lab

Departments

M.I.N.D. Institute
VM Molecular Biosciences

Offices and Labs

3009 VetMed3B
+1 530 754 8603

Profile Introduction

Dr. Giulivi’s expertise is in the area of mitochondria, bioenergetics and free radical biochemistry. This is reflected in >120 publications with more than 7,000 citations in peer-reviewed journals in the chemistry-biochemistry field of mitochondria and free radicals. She has worked on mitochondrial biochemistry since her undergraduate years, and more recently, her focus is on the impact of intermediary metabolism in neurobiology and dietary deficiencies (thiamine), neurodegeneration and neurodevelopmental and neurodegenerative disorders (autism, Huntington’s, fragile X tremor and ataxia syndrome). The effect of gene x environment interaction in autism was explored by using as a model a flame retardant (BDE-49), in which we reported that this additive effect causes a direct disruption of the mitochondrial function at low nM concentrations, further compounded by a genetic background exhibiting a subclinical mitochondrial dysfunction. The study of metabolism in these models is accomplished through the use of a variety of biological models (isolated mitochondria, primary cell culture, established cell cultures, animal models including conditional knock-in and transgenic, human patients’ samples) and using state-of-the art technology (metabolomics, bioinformatics, mitochondrial bioenergetics). Dr. Giulivi has trained a variety of students during the last 20 years, spanning from high-school students (summer internships), undergraduates and graduates to postdoctoral fellows.

Degrees

1989 PhD Biochemistry University of Buenos Aires
1985 Diploma Biochemistry University of Buenos Aires

Research Contribution

My early publications directly addressed the role of oxidative stress in several species (rodents, fish, humans) using isolated mitochondria, isolated cells (epimastigotes of T. cruzi, hepatocytes, macrophages, red blood cells, osteoclasts), organs (liver, lung, intestine), and in vivo models to understand the contribution of antioxidant defenses (enzymatic and non-enzymatic) to the steady-state concentration of reactive oxygen species. Early studies were focused at elucidating the correlation between spontaneous chemiluminescence, a sensitive and non-invasive technique, and steady-state concentrations of reactive oxygen species. Although chemiluminescence emission had been recorded in several systems, the direct correlation with ROS gave a chemical understanding of its production by looking into the biophysical mechanisms of singlet oxygen and triplet carbonyl production during oxidative stress. These publications found that increased rates of production of superoxide anion or hydrogen peroxide were correlated with increased chemiluminescence, how and what antioxidants modulated endogenous oxidative stress, and the main targets of oxidative stress damage in mitochondria. I directly documented the production of nitric oxide by mitochondria in rodent liver and how this endogenous production modulates the affinity of cytochrome oxidase to oxygen. Nitric oxide, by modulating the Km of Complex IV to oxygen, expands the gradient of oxygen within the organ, preventing hypoxia-mediated damage. However, at higher NO production rates –such as those observed with activation of the immune cells-, damage ensues. This damage was evaluated by measuring tyrosine nitration, in which the main intracellular target, was found to be the mitochondrial beta subunit of ATPase. These studies emphasized the role of NO at modulating the availability of oxygen and how this production can also trigger damaging side reactions. Finally, in the last 5-8 years, my laboratory has provided not only evidence of mitochondrial dysfunction in several neurodegenerative and neurodevelopmental disorders such as Huntington’s disease, autism, and fragile X, tremor and ataxia syndrome, but also distinct mechanisms underlying these deficits in bioenergetics. In addition, the effect of gene x environment was further elucidated by using as a model a flame retardant (BDE-49). We reported that this additive causes a direct disruption of the mitochondrial function at low nM concentrations, which is compounded by a genetic background exhibiting a subclinical mitochondrial dysfunction. These studies demonstrate the need to understand basic mechanisms to implement the appropriate therapies or interventions. I have led the biochemical/genetic studies in samples from patients provided by Drs. Hertz-Picciotto, Randi and Paul Hagerman, and Flora Tassone.

Research Interests

Understanding the mitochondrial mechanisms underlying pathophysiology

We explore the mechanisms underlying mitochondrial biology in different pathophysiological cases including autism, schizophrenia, Huntington's and fragile X tremor and ataxia syndrome.

Awards

2010 Autism Science Top 10 Achievement for 2010, for groundbreaking work on identifying mitochondrial dysfunction in autistic children.
2011 NIEHS selected as one of the papers of the year (12/2011; DOI: 10.1001/jama.2010.1706).
2012 NIEHS paper of the month (9/2012; PMID: 3416855).

Department and Center Affiliations

Molecular Biosciences, School of Veterinary Medicine; UC Davis Cancer Center; MIND Institute

ProfessionalSocieties

American Society for Biochemistry and Molecular Biology
Society for Free Radical Research

CBS Grad Group Affiliations

Biochemistry, Molecular, Cellular and Developmental Biology
Integrated Genetics and Genomics

Specialties / Focus

Biochemistry, Molecular, Cellular and Developmental Biology
  • Molecular Medicine
  • Genomics, Proteomics and Metabolomics
  • Biochemistry
  • Molecular Genetics
  • Cellular Responses to Toxins and Stress
  • Molecular Physiology
  • Neurobiology
  • Organelle and Membrane Biology
Integrated Genetics and Genomics
  • Human Genetics and Genomics

Graduate Groups not Housed in CBS

Forensic Science

Labs

Giulivi's laboratory
  • Eleonora Napoli, Ilaria Marsilio, Nikita Shankar, Sarah Rose, and Thu Q. Nguyen

Teaching Interests

Biological Chemistry; Spectroscopy; Bioenergetics; Oxygen and nitrogen free radical biochemistry.

Courses

VetMed VM405 GI and Metabolism
VetMed VM415 Clinical Foundations
PMI 201 Integrative Pathobiology Core I (Winter)
VetMed VM401 Basic Foundations (Fall)

Publications

10/20/2015 11:59:16 AM
  • Giulivi C, Napoli E, Schwartzer J, Careaga M, Ashwood P. Gestational exposure to a viral mimetic poly(i:C) results in long-lasting changes in mitochondrial function by leucocytes in the adult offspring. Mediators Inflamm. 2013;609602. doi: 10.1155/2013/609602. PMID: 24174710; PMCID: 3793312. 

  • Napoli E, Hung C, Wong S, Giulivi C. Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. Toxicol Sci. 2013;132(1):196-210. doi: 10.1093/toxsci/kfs339. PMID: 23288049; PMCID: 3693513. 

  • Napoli E, Wong S, Giulivi C. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism. 2013;4(1):2. doi: 10.1186/2040-2392-4-2. PMID: 23347615; PMCID: 3570390. 

  • Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C. Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One. 2012;7(8):e42504. doi: 10.1371/journal.pone.0042504. PMID: 22900024; PMCID: 3416855. 

  • Napoli E, Duenas N, Giulivi C. Potential therapeutic use of the ketogenic diet in autism spectrum disorders. Front Pediatr. 2014;2:69. doi: 10.3389/fped.2014.00069. PubMed PMID: 25072037; PMCID: 4074854. 

  • Napoli E, Wong S, Hertz-Picciotto I, Giulivi C. Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics. 2014;133(5):e1405-10. doi: 10.1542/peds.2013-1545. PMID: 24753527; PMCID: 4006429. 

  • Villanueva C, Giulivi C. Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. Free radical biology & medicine. 2010;49(3):307-16. PMCID: 2900489.
  • Ross-Inta, C., Tsai, C.-Y., and Giulivi, C. (2008) The mitochondrial pool of free amino acids reflects the composition of mitochondrial-DNA encoded proteins: Indication for a post-translational quality control for protein synthesis. Biosci. Reports 28, 239-49.
  • Giulivi, C., Ross-Inta, C.M., Horton, A., and Luckhart, S. (2008) Metabolic Pathways in Anopheles stephensi mitochondria. Biochem. J. 415, 309-16.
  • DiMarco, T. and Giulivi, C. (2007) Evaluation of analytical methods to detect dityrosine, a biomarker of oxidative stress, in biological samples. Mass Spec. Rev. 26, 108-120.
  • Miller, S., Inta-Ross, C. and Giulivi, C. (2007) Kinetic and proteomic analyses of S-nitrosoglutathione-treated hexokinase: consequences for cancer energy metabolism. Amino acids 32, 593-602.
  • Cooper CE and Giulivi, C. (2007) Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am J Physiol. 292, 1993-2003.
  • Giulivi, C., Kato, K. And Cooper, C. E. (2006) Nitric oxide regulation of mitochondrial oxygen consumption I: cellular physiology. Am. J. Physiol. 291, 1225-1231.
  • Kato K, Giulivi C. (2006) Critical overview of mitochondrial nitric-oxide synthase. Front Biosci. 11:2725-38.
  • Mazzanti, R. and Giulivi, C. (2006) Coordination of nuclear- and mitochondrial-DNA encoded proteins in cancer and normal colon tissues. Biochim Biophys Acta 1757, 618-623.
  • Mazzanti, R., Solazzo, M. Squires, R., Fantappie, O., Cechi, F, Bianchi, P., and Giulivi, C. (2006) Differential expression proteomics of human colon cancer. Am J Physiol 290:G1329-38.
  • Green, A., Rutherford, M. S., Regal, R. R., Flickinger, G. H., Hendrickson, J. A., Giulivi, C., Mohrman, M. E., Fraser, D. G., and Regal, J. F. (2005) Arginase Activity Differs with Allergen in the Effector Phase of Ovalbumin- versus Trimellitic Anhydride-Induced Asthma. Tox. Sci. 88, 420-433.
  • Johnson F, Giulivi C. (2005) Superoxide dismutases and their impact upon human health. Mol Aspects Med. 26, 340-352.
  • Oursler, M. J., Bradley, E., Elfering, S. and Giulivi, C. (2005) Native, not nitrated, cytochrome c and mitochondrial-derived hydrogen peroxide drive osteoclast apoptosis. Am., J. Physiol. 288, C156-168.
  • Haynes, V., Elfering, S. L., Squires, R., Traaseth, N., Solien, J., Ettl , A. and Giulivi, C. (2004) Mitochondrial Nitric-Oxide Synthase: Role in Pathophysiology. IUBMB Life 55, 599-603.
  • Traaseth, N, Elfering, S. L., Solien, J., Haynes, V., and Giulivi, C. (2004) Role of Calcium Signaling in the Activation of Mitochondrial Nitric-Oxide Synthase and Citric Acid Cycle. Biochim. Biophys. Acta 1658, 64-71.
  • Haynes, V., Elfering, S. L., Traaseth, N., and Giulivi, C. (2004) Mitochondrial Nitric-Oxide Synthase: Enzyme expression, characterization and regulation. J. Bioenerg. Biomemb. 36, 341-346.
  • Elfering, S. L., Haynes, V., Traaseth, N., Ettl, A. and Giulivi, C. (2004) Aspects, mechanism, and biological relevance of mitochondrial protein nitration sustained by mitochondrial nitric oxide synthase. Am. J. Physiol. 286, H22-H29.
  • Xiong, S., She, H., Takeuchi, H., Engelhardt, J. F., Barton, C. H., Zandi, E., Giulivi, C., and Tsukamoto, H. (2003) Signaling role of intracellular iron in NF-kB activation. J. Biol. Chem. 278, 17646-54.
  • Giulivi, C. (2003) Characterization and function of mitochondrial nitric-oxide synthase. Free Radical Biol. Med. 34, 397-408.
  • Giulivi, C, Traaseth, N. J., and Davies, K. J. A. (2003) Tyrosine oxidation products: analysis and biological relevance. Amino Acids 25, 227-232.
  • Elfering, S. L., Sarkela, T. M. and Giulivi, C. (2002) Biochemistry of mitochondrial nitric oxide synthase. J. Biol. Chem. 277, 38079-38086.
  • Sarkela, T., Berthiaume, J., Elfering, S., Gybina, A. and Giulivi, C. (2001) The modulation of oxygen radical production by endogenous nitric oxide in mitochondria. J. Biol. Chem. 276, 6945-6949.
  • Steffen, M., Sarkela, T.M., Gybina, A.A., Steele, T.W., Traaseth, N. J., Kuehl, D. and Giulivi, C. (2001) Metabolism of S-nitrosoglutathione in intact mitochondria. Biochem. J. 356, 395-402.
  • French, S., Giulivi, C., and Balaban, R. S. (2001) Nitric oxide synthase in porcine heart mitochondria: Evidence for a low physiological activity. Am. J. Physiol. 280, H2863-7.
  • Lizarralde MS, Bailliet G, Poljak S, Fasanella M, Giulivi C. Assessing genetic variation and population structure of invasive North American beaver (Castor Canadensis Kuhl, 1820) in Tierra Del Fuego (Argentina). Biological Invasions. 2008;10(5):673-83.
  • Fujisawa Y, Kato K, Giulivi C. Nitration of tyrosine residues 368 and 345 in the beta -subunit elicits F0F1-ATPase activity loss. Biochem J. 2009;423(2):219-31.
  • Ross-Inta CM, Zhang YF, Almendares A, Giulivi C. Threonine-deficient diets induced changes in hepatic bioenergetics. American journal of physiology. 2009;296(5):G1130-9. PMCID: 2696218.
  • Giulivi C, Zhang Y-F, Omanska-Klusek A, Ross-Inta CM, Wong S, Hertz-Picciotto I, et al. Mitochondrial dysfunction in autism. JAMA. 2010;304:2389-96.
  • Haynes V, Traaseth NJ, Elfering S, Fujisawa Y, Giulivi C. Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging. Am J Physiol Endocrinol Metab. 2010;298(5):E978-87. PMCID: 2867368.
  • Perez CJ, Jaubert J, Guenet J-L, Barnhart KF, Ross-Inta CM, Quintanilla VC, et al. Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes. American Journal of Pathology. 2010;177(4):1958-68.
  • Ross-Inta C, Omanska-Klusek A, Wong S, Barrow C, Garcia-Arocena D, Iwahashi C, et al. Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. The Biochemical journal. 2010;429(3):545-52.
  • Giulivi C, Ross-Inta C, Omanska-Klusek A, Napoli E, Sakaguchi D, Barrientos G, et al. Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice. Journal of Biological Chemistry. 2011;286(1):99-113.