Professor of Biological Chemistry
Johns Hopkins University School of Medicine
JHU School of Medicine
725 N. Wolfe St. 400 Biophysics
Office Phone: 410-955-3827
Lab Phone: 410-955-3167
Lab Web Site
|Click Here for PDF of CV|
Cell energetics, its molecular and chemical basis and relationship to both disease (Cancer/Heart) and to the discovery of new therapies.
In addition to studies focused on elucidating the structure, mechanism, and regulation of the mammalian mitochondrial ATP synthase, a major disease focus of the Pedersen lab for many years has been cancer because of its well known alterations in energy metabolism. More recently, we have entered also into a study of heart dysfunction as the heart with every beat is totally dependent on energy metabolism, with the mitochondrial ATP synthase being intimately involved.
The laboratory uses chemistry, molecular biology, biophysics, immunology, tissue culture and animal models to better understand the energetics/energy metabolism of normal and pathological cells/tissues. A major focus is on the two 'power plants', the mitochondria and the glucose catabolic system (glycolysis), as well as on the interaction between these two systems. The following are active research projects.
1) The mechanism and regulation of ATP synthesis in mammalian mitochondria.
This involves the study of the molecular properties of the ATP synthase complex that consists of two nano-motors both of which are necessary to make ATP. In a collaborative study we have obtained the 3-D structure of one of the motors and are now working on the structure of the whole complex that consists of 17 subunit types and over 30 total subunits.
Recently, we discovered that the ATP synthase is in complex formation with the transport system (carrier) for phosphate and the transport system for adenine nucleotides (ADP and ATP). We have named this complex the ATP Synthasome and are now carrying out studies to obtain a 3-D structure of the whole complex. It is important to note that the ATP synthasome represents the terminal complex of oxidative phosphorylation in mitochondria and makes most of the ATP needed/day to supply our energy needs.
In addition to the above mentioned work, we have also recently discovered that the ATP synthasome contains another key protein originally thought to be within the outer membrane as well as at contact sites between inner and outer membranes. This protein is likely critical for channeling ATP to the cytoplasm.
Work on the ATP synthasome is being vigorously studied.
2) Cancer: Regulation and targeting genes and proteins responsible for the most common phenotype and developing a novel potent anticancer agent, 3-bromopyruvate (3BP).
The most common metabolic phenotype of malignant cells & tumors including those derived from liver, breast, lung, brain, etc. is their capacity to utilize glucose at high rates even in the presence of oxygen. The pivotal enzyme involved is hexokinase 2 (HK-2) that is markedly elevated and bound at or very near the outer mitochondrial membrane protein named "VDAC" (voltage dependent anion channel). At this location, hexokinase 2 not only helps couple ATP formation in mitochondria to the phosphorylation of glucose to "jump start"glucose catabolism, it also represses this organelle's contribution to cell death. Therefore, hexokinase 2, in addition to its critical metabolic role, also promotes cancer by helping immortalize cancer cells. We are studying both the hexokinase 2 gene and developing novel strategies to target both the gene and the protein. We use both tumor cells growing in tissue culture and animal models, i.e., animals with cancer.
While working in my laboratory at the beginning of this century Dr. Young Ko discovered that the small molecule 3-bromopyruvate (3BP) is a potent anticancer agent. Several years later while working as a new faculty member in collaboration with my laboratory she would lead a team that showed 3BP's capacity to completely cure (eradicate) cancers in 19 out of 19 treated animals, i.e.,100%.
Currently, in collaboration with Dr. Ko, we are now involved in the further development of 3BP while searching for other effective anticancer agents. A limited number of studies conducted in humans with 3BP have proved very promising.
3) Heart Dysfunction: Regulation of the mitochondrial ATP synthase in the normal and ischemic heart.
The heart can survive only short periods without oxygen. Conditions where oxygen is limiting can have grave consequences as the mitochondrial membrane potential will collapse and the mitochondrial ATP synthase will switch from synthesizing ATP to hydrolyzing ATP, thus depleting heart cells (cardiomyocytes) of the energy reserves they require for survival. Fortunately, the ATP synthase is well regulated in the heart so that the ATP hydrolytic event is minimized during short periods of ischemia (reduced oxygen). In fact, there are 3 known small peptide regulators of the ATP synthase, one which optimizes ATP synthesis and the other two that suppress ATP hydrolysis. In addition, the ATP synthase is subjected to regulatory signal transduction events that result either in its phosphorylation or dephosphorylation.
We are currently involved in a project designed to understand the relative importance of these and other regulatory events in protecting the heart during sudden ischemic insults.
[The laboratory has published over 240 papers of which >150 describe original research while the others refer either to novel methods or represent reviews]
Azevedo-Silva J, Queirós O, Ribeiro A, Baltazar F, Young KH, Pedersen PL, Preto A, Casal M. The cytotoxicity of 3-Bromopyruvate in breast cancer cells depends on extracellular pH. Biochem J. 2015 Feb 2. [Epub ahead of print]
Majkowska-Skrobek G, Augustyniak D, Lis P, Bartkowiak A, Gonchar M, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S. Killing multiple myeloma cells with the small molecule 3-bromopyruvate: implications for therapy. Anticancer Drugs. 2014 Jul;25(6):673-82.
Dyląg M, Lis P, Niedźwiecka K, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S. 3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans. Biochem Biophys Res Commun. 2013
Darpolor MM, Kaplan DE, Pedersen PL, Glickson JD. Human Hepatocellular Carcinoma Metabolism: Imaging by Hyperpolarized 13C Magnetic Resonance Spectroscopy. J Liver Disease Transplant. 2012 Sep 1;1(1).
Pedersen PL. Mitochondria in relation to cancer metastasis: introduction to a mini-review series. J Bioenerg Biomembr. 2012 Dec;44(6):615-7.
Pedersen PL. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue. J Bioenerg Biomembr. 2012 Feb;44(1):1-6.
Lis P, Zarzycki M, Ko YH, Casal M, Pedersen PL, Goffeau A, Ułaszewski S. Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae. J Bioenerg Biomembr. 2012.
Queirós O, Preto A, Pacheco A, Pinheiro C, Azevedo-Silva J, Moreira R, Pedro M, Ko YH, Pedersen PL, Baltazar F, Casal M. Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. J Bioenerg Biomembr. 2012 Feb;44(1):141-53.
Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL. A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr. 2012 Feb;44(1):163-70.
Blum DJ, Ko YH, Pedersen PL. Mitochondrial ATP synthase catalytic mechanism: a novel visual comparative structural approach emphasizes pivotal roles for Mg²⁺ and P-loop residues in making ATP. Biochemistry. 2012 Feb 21;51(7):1532-46.