Norma Frizzell, PhD
University of Ulster, N. Ireland,
University of South Carolina
PhD: The Queens University of Belfast, N. Ireland
BSc: Biochemistry - The Queens University of Belfast, N. Ireland
Our laboratory is interested in a recently discovered post-translational modification of proteins known as S-(2-succino)cysteine (2SC), also termed protein succination. Protein succination occurs when fumarate (from the Krebs cycle) reacts with cysteines to form the irreversible modification 2SC.
While we have studied this modification extensively in the adipocyte during diabetes, we are also interested in other conditions which lead to increased fumarate – including cancers derived from mutations in the gene for fumarate hydratase.
We are currently 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. We hypothesize that protein succination is an important metabolic link between fuel excess and cellular dysfunction. For example, the hormone adiponectin is succinated during diabetes, preventing its secretion from the adipocyte (JBC 284(38):25772-81).
Our laboratory is specifically interested in how protein succination may interfere with the function of important chaperone proteins in the endoplasmic reticulum (ER). As a consequence of this the cell may have impaired protein folding and an accumulation of misfolded proteins leading to ER stress. We use a combination of cell culture and animal models and a range of cellular and biochemical techniques to investigate the importance of succination in understanding how nutrient excess triggers the development of diabetes. Additionally we are interested in therapeutic strategies which may lower protein succination by lowering mitochondrial stress in the adipocyte.
- 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 Feb;15(2):445-61
- 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 Jan;1853(1):213-21.
- Piroli GG, Manuel AM, Walla MD, Jepson MJ, Brock JW, Rajesh MP, Tanis RM, Cotham WE, Frizzell N.
Identification of protein succination as a novel modification of tubulin.
Biochem J. 2014 Sep 1;462(2):231-45.
- Merkley ED, Metz TO, Smith RD, Baynes JW, Frizzell N.
The succinated proteome.
Mass Spectrom Rev. 2014 Mar-Apr;33(2):98-109
- Manuel AM, Frizzell N.
Adipocyte protein modification by Krebs cycle intermediates and fumarate ester-derived succination.
Amino Acids. 2013 Nov;45(5):1243-7.
- Frizzell N, Thomas SA, Carson JA, Baynes JW.
Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity.
Biochem J. 2012 Jul 15;445(2):247-54.