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
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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]
Mathupala, S.P., Ko, Y.H., and Pedersen, P.L. (2010) The Pivotal Roles of Mitochondria in Cancer: Warburg and Beyond and Encouraging Prospects for Effective Therapies. Biochimica et Biophysica Acta, In Press.
Mathupala, S.P., Ko, Y.H., and Pedersen, P.L. (2009) Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy. Semin. Cancer Biol. 19, 17-34.
Pedersen, P.L. (2009) Mitochondrial Matters of the Heart: A Plethora of Regulatory Modes to Maintain Function for a Long Lifetime. J. Bioenerg. Biomemb. 41, 95-98.
Pedersen, P.L. (2008) Voltage Dependent Anion Channels (VDACs): A Brief Introduction with a Focus on the Outer Mitochondrial Compartment's Role together with Hexokinase-2 in the "Warburg Effect" in Cancer. J. Bioenerg. Biomemb. 40, 123-126.
Hong, S. and Pedersen, P.L. (2008) ATP Synthase and the Actions of Inhibitors Utilized to Study Its Roles in Human Health, Disease, and Other Scientific Areas. Microbiol. Mol. Biol. Rev. 72, 590-641.
Pedersen, P. L. (2007) The Cancer Cell's "Power Plants" as Promising Therapeutic Targets: An Overview. J. Bioenerg. Biomemb., 39, 1-12.
Pedersen, P.L. (2007) Warburg, Me and Hexokinase 2: Multiple Discoveries of Key Molecular Events Underlying One of Cancers' Most Common Phenotypes, the "Warburg Efect", i.e., Elevated Glycolysis in the Presence of Oxygen. J. Bioenerg. Biomemb., 39, 211-222.
Pedersen, P.L. (2007) Transport ATPases into the Year 2008: A Brief Overview Related to Types, Structures Functions and Roles in Health and Disease. J. Bioenerg. Biomemb. 39, 349-355.
Mathupala, S. P., Ko, Y.H., and Pedersen, P. L. (2006) Hexokinase II: Cancer's Double-Edged Sword Acting as Both Facilitator and Gatekeeper of Malignancy when Bound to Mitochondria. Oncogene, 25,4777-4786.
Blum, D.J., Ko, Y.H., and Pedersen, P.L. (2011) Mitochondrial ATP Synthase Catalytic Mechanism: A Novel Bioinformatics Approach Emphasizes Pivotal Roles for Mg2+ and P-Loop Residues Beta A-158 and Beta-T163 in making ATP. Biochemistry, 2012 Feb 21;51(7):1532-46.
Tao, J., Ko, Y.H., and Pedersen, P.L. (2010) Release of MBD2 and DNMT1 from the Hexokinase 2 Promoter Activates Gene Expression in Cancer Cells. To be submitted.
Arrell, D. K., Elliott, S.T., Guo, Y., Kane, L.A., Ko, Y. H., Pedersen, P. L., Robinson, J., Murata, M., Murphy, A. M., Marban, E., and Van Eyk, J. F. (2006) Proteomic Analysis of Pharmacological Preconditioning: Novel Protein Targets Converge to Mitochondrial Metabolism Pathways. Circ. Res. 29, 706-714.
Chen, C., Saxena, A.J., Simcoke, W. N., Garboczi, D. N., Pedersen, P.L., and Ko, Y.H. (2006) Mitochondrial ATP Synthase: Crystal Structure of the Catalytic Unit in a Vanadate-Induced Transition-Like State and Implications for Mechanism, J. Biol. Chem., 281, 13777-13783.
Chen C., Ko Y.H., Delannoy, M., Ludtke S.J., Chiu W., Pedersen P.L. (2004). Mitochondrial ATP Synthasome: Three Dimensional Structure by Electron Microscopy of the ATP Synthase in Complex Formation with Carriers for Pi and ADP/ATP. J Biol Chem; 279:31761-8.
Hong, S.J. and Pedersen, P.L. (2004). A Bioinformatic Approach Reveals New Insights About the Roles of Supernumerary Subunits g and A6L. J Bioenerg. Biomemb. 36(6):515-23.
Ko Y.H., Smith B.A., Wang Y., Pomper M.G., Rini D.A., Torbenson M.S., Hullihen J., Pedersen P.L. (2004). Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun; 324: 269-275.
Ko, Y.H., Delannoy, M., Hullihen, J., Chiu, W., and Pedersen, P.L. (2003) Mitochondrial ATP synthasome. Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J. Biol. Chem. 278, 12305-12309.
Goel, A., Lee, M.G., Mathupala, S.P., and Pedersen, P.L. (2003) Glucose Metabolism in Cancer: Evidence that Demethylation Events Play a Role in Activating Type II Hexokinase Gene Expression. J. Biol. Chem., 278, 15333-15340.
Lee, M.G. and Pedersen, P.L. (2003) Glucose Metabolism in Cancer: Importance of Transcription Factor-DNA Interactions within a Short Segment of the Proximal Region of the Type II Hexokinase Promoter. J. Biol. Chem. 278(42):41047-58.
Three other papers (not listed) are also nearly complete and to be submitted.