Faculty and Staff
Norma Frizzell, PhD
|Title:||Associate Professor of Pharmacology, Physiology & Neuroscience
|Department:||Pharmacology, Physiology & Neuroscience
School of Medicine
Pharmacology, Physiology & Neuroscience
Biochemistry - The Queens University of Belfast, N. Ireland
The Queens University of Belfast, N. Ireland
University of Ulster, N. Ireland,
University of South Carolina
Our laboratory is interested in the chemical modification of proteins by mitochondrial metabolites, with a particular focus on the succination of proteins by the Krebs cycle intermediate fumarate. Fumarate reacts with protein thiols to form the irreversible modification S-(2-succino)cysteine (2SC).
We are investigating the mechanisms of glucotoxicity in the adipocyte in order to understand the association between mitochondrial stress and an increase in protein succination. During diabetes nutrient excess leads to an increase in fumarate and 2SC in the adipocyte, as a result the diabetic adipocyte contains many modified proteins with altered structure and/or function. Protein succination appears to be an important metabolic link between fuel excess during diabetes and the onset of cellular dysfunction. For example, the hormone adiponectin is succinated during diabetes, preventing its secretion from the adipocyte.
We are also interested in the role of fumarate and protein succination in mitochondrial encephalopathies and fumarase deficient cancers. We have described for the first time how metabolic alterations lead to increased brainstem and olfactory bulb succination in a murine model of Leigh Syndrome and are currently investigating several protein targets whose structure/function is altered as a consequence of this.
- Piroli GG, Manuel AM, Patel T, Walla MD, Shi L, Lanci SA, Wang J, Galloway A, Ortinski PI, Smith DS, Frizzell N. Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization. Mol. Cell. Proteomics. 2018 (in press).
- Manuel AM, Walla MD, Faccenda A, Martin SL, Tanis RM, Piroli GG, Adam J, Kantor B, Mutus B, Townsend DM, Frizzell N. Succination of Protein Disulfide Isomerase Links Mitochondrial Stress and Endoplasmic Reticulum Stress in the Adipocyte During Diabetes. Antioxid. Redox Signal. 2017 27:1281-1296.
- McCain R, Patel T, Piroli GG, Frizzell N. Stressful Situations: Mitochondrial Metabolism & the Accumulation of Fumarate, IMARS Highlights 2017 12:4 (invited commentary)
- Adam J, Ramracheya R, Chibalina MV, Ternette N, Hamilton A, Tarasov AI, Zhang Q, Rebelato E, Rorsman NJG, Martín-Del-Río R, Lewis A, Özkan G, Do HW, Spégel P, Saitoh K, Kato K, Igarashi K, Kessler BM, Pugh CW, Tamarit-Rodriguez J, Mulder H, Clark A, Frizzell N, Soga T, Ashcroft FM, Silver A, Pollard PJ, Rorsman P. Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes. Cell Rep. 2017 20:3135-3148
- Ruecker N, Jansen R, Trujillo C, Puckett S, Jayachandran P, Piroli GG, Frizzell N, Molina H, Rhee KY, Ehrt S. Fumarase Deficiency Causes Protein and Metabolite Succination and Intoxicates Mycobacterium tuberculosis. Cell Chem Biol. 2017 3:306-315
- Piroli GG, Manuel AM, Clapper AC, Walla MD, Baatz JE, Palmiter RD, Quintana A, Frizzell N. Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome. Mol Cell Proteomics. 2016 15:445-461
- Yang H, Wu JW, Wang SP, Severi I, Sartini L, Frizzell N, Cinti S, Yang G, Mitchell GA. Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis and Insulin Resistance. Diabetes 2016
- Tanis RM, Piroli GG, Day SD, Frizzell N. The effect of glucose concentration and sodium phenylbutyrate treatment on mitochondrial bioenergetics and ER stress in 3T3-L1 adipocytes. Biochim Biophys Acta. 2015 1853:213-221
- Gerardo G Piroli, Matthew J Jepson, Allison M Manuel, Michael D Walla, Jonathan WC Brock, Mathur P Rajesh, William E Cotham, Norma Frizzell. Identification of Protein Succination as a Novel Modification of Tubulin. Biochem J. 2014 462:231-245
- Merkley ED, Metz TO, Smith RD, Baynes JW, Frizzell N. The Succinated Proteome. Mass Spectrom. Rev. 2014 33:98-109. (Invited Review)
Current Lab Members
- Dr. Gerardo Piroli: Research Assistant Professor
- Richard McCain: Graduate Researcher
- Stephanie Martin: Graduate Researcher
- Holland Smith: Research Specialist
- Tulsi Patel: Undergraduate Researcher
- Macey Johnson: Undergraduate Researcher
- Bryan Fitzgerald: Undergraduate Researcher