Education

BSc
Biochemistry - The Queens University of Belfast, N. Ireland 

PhD
The Queens University of Belfast, N. Ireland  

Postdoctoral
University of Ulster, N. Ireland,
University of South Carolina

Research

Our laboratory is interested in the chemical modification of proteins by mitochondrial metabolites, and understanding the conditions that govern metabolite reactivity. We have a particular focus on the succination of proteins by the Krebs cycle intermediate fumarate. Fumarate reacts non-enzymatically with protein cysteine thiols to form the irreversible modification S-(2-succino)cysteine (2SC).

We are investigating the role of fumarate and protein succination in mitochondrial encephalopathies derived from defects in the electron transport chain machinery. 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. We are currently examining several protein targets whose structure and function is altered as a consequence of succination. This has revealed intracellular defects beyond the electron transport chain, and has informed new avenues of therapeutic intervention that we anticipate will benefit Leigh Syndrome patients.

We also have a longstanding interest in understanding how mitochondrial stress in the adipocyte contributes to increased protein succination, and we were the first laboratory to document and study the impact of succination on specific adipocyte proteins. 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.

 

Recent Publications

• Piroli GG, Manuel AM, Smith HS, McCain RS, Cotham W, Walla MD, Frizzell N# (2021) Succination of Dihydrolipoyllysine Succinyltransferase Exacerbates Mitochondrial ATP Deficiency in a Mouse Model of Leigh Syndrome. Available on BioRxiv: https://www.biorxiv.org/content/10.1101/2020.01.09.900514v1
• Manuel AM, Walla MD, Dorn MT, Tanis RM, Piroli GG, Frizzell N. Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte. Free Radic Biol Med. 2020 Feb 20;148:70-82.
• 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. 2019 18(3):504-519.
• Kulkarni RA, Bak DW, Wei D, Bergholtz SE, Briney CA, Shrimp JH, Alpsoy A, Thorpe AL, Bavari AE, Crooks DR, Levy M, Florens L, Washburn MP, Frizzell N, Dykhuizen EC, Weerapana E, Linehan WM, Meier JL. A chemoproteomic portrait of the oncometabolite fumarate. Nat Chem Biol. 2019 Apr;15(4):391-400.
• 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.
• 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

Find Dr. Frizzell on Pubmed.

Current Lab Members

• Dr. Gerardo Piroli: Research Assistant Professor
• Holland Smith: Research Specialist